Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice

Management Update

ManageMent Update Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice Sashi S. Kommu, BSc(Hons), MBBS,1,6 Robert McArthur, BA(Hons), PGCE,2,6 Amr M. Emara, MBBS,1,6,7 Utsav D. Reddy, MBBS,1 Christopher J. Anderson, MBChB,3,6 Neil J. Barber, BSc, MBBS,1,6 Raj A. Persad, MBBS,4,6 Christopher G. Eden, MBBS, MS5,6 1Frimley Park Hospitals NHS Foundation Trust, Frimley, United Kingdom; 2St George’s, University of London, London, United Kingdom; 3St George’s Hospital, London, United Kingdom; 4Bristol Urological Institute and The University of Bristol, Bristol, United Kingdom; 5Royal Surrey County Hospital, Guildford, Surrey, United Kingdom; 6STILUS Academic Research Group, London, United Kingdom; 7Urology Department, Ain Shams University, Cairo, Egypt There has been a recent and near exponential increase in the use of hemostatic agents and sealants to supplement the rapidly evolving methods in the surgical management of urologic patients. This article reviews the use of hemostatic agents and sealants in current urologic practice. [Rev Urol. 2015;17(3):150-159 doi: 10.3909/riu0673] ® © 2015 MedReviews , LLC Key words Hemostasis • Tissue adhesion • Urologic surgery T he manner in which hemostasis and tissue adhesion is achieved intraoperatively is critical to improving the outcomes of urologic surgery. Innovation in other surgical specialties has led to the development of a variety of topical biologic agents that locally enhance the clotting cascade to achieve either hemostasis, tissue adhesion, or both. Although many are routinely being used in a variety of surgical subspecialties, the benefits of hemostatic agents are rarely demonstrated due to the lack of well-designed clinical trials. The ideal hemostatic agent must achieve instant closure of blood vessels without damage to surrounding tissues, is immunologically inert, and must maintain the tissue seal until vascular obliteration and tissue healing occurs. The utility of hemostatic agents, therefore, extends from any type of elective surgery to emergency surgical procedures. The agents used can be broadly classified into topical hemostatic agents, tissue sealants, and tissue adhesives. There are several published review articles that specifically look at the different types and 150 • Vol. 17 No. 3 • 2015 • Reviews in Urology 4004170006_RIU0673.indd 150 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice indications of these agents; here, we present a summary with a particular focus on their utility in urologic surgery (Table 1). Topical Hemostatic Agents Topical hemostatic agents are designed to achieve hemostasis by promoting clot formation through the activation of the clotting cascade. They come in a variety of forms, ranging from sponge-type materials to liquids. The liquid forms are suitable in cases of limited blood loss, in which the agent will remain in one place. If blood loss is large, solid agents can be applied to the bleeding surface, with or without pressure to enhance the clotting of the surrounding tissue and vessels. One such group is fibrin sealants, which contain fibrinogen and thrombin (these have approval for use as topical hemostatic agents, tissue sealants, and tissue adhesives). The concentration of fibrinogen determines the clot strength, and the concentration of thrombin determines the rate of clot formation.1 Unlike other hemostatic agents, fibrin sealants do not rely on the presence of blood or serum for clot formation. Tissue Sealants Sealants are agents that can prevent the leakage of fluids by providing a physical barrier, which also aids in hemostasis. One example is polyethylene glycol (PEG) polymer, which is used for vascular sealing and sealing of the dura. Albumin with glutaraldehyde has a role in sealing of large vessel anastomoses. Adhesives Adhesives are agents that glue tissues together, such as cyanoacrylate, which is used for topical external use (eg, skin lacerations). Fibrin sealants have been approved for use in the attachment of skin grafts to underlying tissue in the place of staples. Albumin with glutaraldehyde has been approved as in laparoscopic or robotic partial nephrectomies. Topical hemostatic agents are feasible alternatives to traditional methods of hemostasis, as they can Albumin with glutaraldehyde has been approved as an adhesive for the different arterial wall layers in aortic surgery. an adhesive for the different arterial wall layers in aortic surgery.2 Renal Surgery: Nephronsparing Surgery and Nephrectomy Current data suggest that, due to advances in detection, approximately 60% of renal tumors are detected at stage T1N0M0. This trend has led to an increase in easily be applied through laparoscopic port sites. One of the first case series of laparoscopic partial nephrectomy utilized hemostatic glue consisting of gelatin, resorcinol, and formaldehyde, in combination with other hemostatic devices, and concluded that use of biologic glue enhanced the process of hemostasis.6 Another case series reported the safety of a two-component gelatin matrix hemostatic One of the first case series of laparoscopic partial nephrectomy utilized hemostatic glue consisting of gelatin, resorcinol, and formaldehyde, in combination with other hemostatic devices, and concluded that use of biologic glue enhanced the process of hemostasis. the number of patients undergoing nephron-sparing surgery.3 A partial nephrectomy is a common urologic procedure performed for small renal tumors in patients with preexisting renal failure or solitary kidney, when preservation of nephrons is paramount. Reducing the ischemia time arising from clamping of the renal hilum is an important aim during surgery, as longer ischemia times are thought to be associated with longer renal function recovery times.4 In conventional open partial nephrectomy, application of ice to the kidney reduces the parenchymal temperature, which has an effect of extending the threshold of ischemia time.5 A combination of sutures, bolsters, electrocautery, and argon laser is available to achieve reliable hemostasis, assisting an early exit from ischemia. The routine use of ice and other agents is often limited ® agent (Floseal Hemostatic Matrix; Baxter Healthcare, Deerfield, IL) as the sole hemostatic agent in cases of open or laparoscopic partial nephrectomy after hilar clamping.7 The authors reported that Floseal provided an immediate and durable effect in controlling bleeding with no significant perirenal hematoma formation in all 25 patients studied. Using a similar gelatin matrix hemostatic agent and technique, Bak and colleagues8 showed satisfactory and rapid hemostasis after 1 to 2 minutes in all 6 cases, with a warm ischemia time ranging between 10 and 14 minutes. Similar results were shown in a larger cohort by Gill and colleagues9; they found the Floseal-treated group had significantly fewer complications. In a study on 12 pigs, Ploussard and associates10 concluded that the use of Floseal with concurrent TISSEEL (Baxter Healthcare) ® Vol. 17 No. 3 • 2015 • Reviews in Urology • 151 4004170006_RIU0673.indd 151 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice continued TABLe 1 Hemostatics and Sealants in Urologic Surgical Practice Product Mode Description Possible Uses in Urologic Surgery BioGlue® Surgical Adhesive Adhesive (CryoLife, Kennesaw, GA) Bovine serum albumin and glutaraldehyde Aortic surgery: adhesive and sealant of different arterial wall layers22 Surgicel® (Ethicon, Hemostatic agent Somerville, NJ) Absorbable cotton and oxidized regenerated cellulose Hemostatic Floseal® Hemostatic Matrix agent (Baxter Healthcare, Deerfield, IL) Bovine-derived gelatin matrix and human-derived thrombin Nephron-sparing surgery: better postoperative renal function compared with standard suture closure22 Parenchymal renorrhaphy: temporary packing for control of capillary, venous, or small arterial hemorrhage37 PCNL: no significant difference in urinary extravasation rates37 Open and laparoscopic partial nephrectomy: enhances process of hemostasis7; satisfactory and rapid hemostasis after 1-2 min and warm ischemia time ranging from 10-14 min8; enhances parenchymal hemostasis and decreases hemorrhagic complications9; allows clamp-free tumor excision in laparoscopic nephrectomy for small peripheral tumours19; effective in hypertensive (200 mm Hg systolic) porcine partial nephrectomy when used in combination with sutured bolster20; decreased warm ischemia time during laparoscopic partial nephrectomy21; less tissue necrosis when no suturing in laparoscopic partial nephrectomy21 Renal trauma: superior to sutured gelatin sponge bolsters in reducing intraoperative blood loss and time to achieve hemostasis45 TISSEEL® (Baxter Healthcare) Sealant Fibrin sealant consisting of fibrinogen and thrombin derived from human plasma Nephrectomy: repair of collecting system injuries12,13; helps avoid hilar clamping during laparoscopic partial nephrectomy17 PCNL: no difference in postoperative hematocrit, pain, infection, or urinary leakage rates, possible shorter hospital stay, and no detectable difference in blood loss compared with nephrostomy tube29,30,35; tract sealing time 2-5 min31 Pyeloplasty: contradictory evidence: superior to GRF glue and laser tissue welding when leak pressures and operating times evaluated at higher leak pressures than conventional suturing techniques41; shorter operative time and postoperative hospital stay, and less analgesia requirements compared with sutured controls42; no benefit over sutured pyeloplasty, with associated urinoma formation and ureteric obstruction43 Coagulum pyelolithotomy: reduced incidence of incomplete stone removal in classic or robotic laparoscopic transperitoneal dismembered ureteropyloplasty44 Complex pendulous urethral stricture anastomosis: appears to promote wound healing and enable earlier catheter removal51 152 • Vol. 17 No. 3 • 2015 • Reviews in Urology 4004170006_RIU0673.indd 152 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice TABLe 1 Hemostatics and Sealants in Urologic Surgical Practice (Continued ) Product Mode Description COSEAL Surgical Sealant (Baxter Healthcare) Sealant PEGs, dilute Nephron-sparing surgery: better postoperative renal function hydrogen compared with standard suture closure22 chloride solution, and sodium phosphate/ sodium carbonate solution TachoSil® (Baxter Healthcare) Hemostatic agent Equine collagen, human thrombin, and human fibrinogen PCNL: reduction in urinary leakage rate and hospital stay, with no difference in analgesic requirements or pain scores, compared with nephrostomy tube32,33 SPONGOSTAN™ Absorbable Haemostatic Gelatin Sponge (Ethicon) Hemostatic agent Absorbable hemostatic porcine gelatin sponge PCNL: less operative pain, lower urinary extravasation rates, and shorter hospital stay without detectable difference in blood loss when used in conjunction with tubeless PCNL compared with tubeless PCNL on its own36 Glubran 2™ Surgical (MediVogue, Saint- glue with Jérôme, Quebec) hemostatic, adhesive, sealant, and bacteriostatic properties N-butyl-2cyanoacrylate (monomer) and metacryloxysulpholane (monomer) Upper and lower urinary tract fistulas: suitable for endoscopic, percutaneous, and endovaginal use with reduced hospital stay time and time to recovery50 Hemaseel APR™ –discontinued (Haemacure Corporation, Montréal, Québec) Fibrin sealant consisting of fibrinogen and thrombin derived from human plasma Renal trauma: when used in conjunction with bandages pretreated with thrombin, was found to be superior to sutured gelatin sponge bolsters in reducing intraoperative blood loss and time to achieve hemostasis in porcine stab wounds46 Sealant Possible Uses in Urologic Surgery Simple retropubic prostatectomy: adjunctive use instead of pelvic drainage is safe and effective47 Reconstruction of Fournier gangrene sequelae: useful adjunct for managing complex wounds49 Product brand name not defined Adhesive Biologic surgical GRF glue Laparoscopic retroperitoneal partial nephrectomy: simplifies hemostasis and closure of the collecting system but good quality drainage provides additional safety10 Product brand name not defined Sealant Fibrin sealant consisting of fibrinogen and thrombin Total or partial nephrectomy: stops hematuria from the ureteric remnant endoscopically52 Product brand name not defined Sealant PEG polymer Laparoscopic partial nephrectomy: safe and effective for long-term sealing in porcine models with no detectable humoral or cell-mediate immune response after 2 wk11 GRF, gelatin-resorcin-formalin; PCNL, percutaneous nephrolithotomy; PEG, polyethylene glycol. Vol. 17 No. 3 • 2015 • Reviews in Urology • 153 4004170006_RIU0673.indd 153 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice continued sealant was sufficient to control major medullary vascular injuries and replace conventional sutures without compromising operative outcomes in deep one-third partial nephrectomy. Hemostatic agents often contain nonhuman components which must be shown to be immunologically inert to minimize the risks of (n 5 25). Overall, postoperative hemorrhage or urine leakage occurred in 9% and 2% of patients, respectively. Moreover, in patients with known collecting system injury, 7 of 17 patients in group 1 (41%) had hemorrhage or leakage, in contrast to 2 of 18 patients in group 2 (11%; P 5 .04). Although the use of Hemostatic agents often contain nonhuman components, which must be shown to be immunologically inert to minimize the risks of secondary hemorrhage, infection, inflammation, and nephron loss. secondary hemorrhage, infection, inflammation, and nephron loss. Immunologic response to hemostatic agents has been studied by Park and associates11 who investigated the long-term consequences of PEG-based hydrogel tissue sealant in a porcine model, showing no detectable humoral or cellmediated immune response after 2 weeks without deleterious effects to renal tubules. Repair of collecting system injuries during partial nephrectomy using tissue sealants has also been described.12 Tissue sealants have the effect of rapidly sealing two edges of tissue, in addition to hemostatic effects. Although unsuitable in arterial bleeding, in which the sealant can be washed away, effective sealing of the collecting system prevents urinoma formation and reduces the need for suturing, which may increase the warm ischemia time. Johnston and colleagues13 compared the efficacy of TISSEEL in achieving hemostasis and collecting system repair against standard sutured bolsters prospectively in 100 cases of nonrandom consecutive laparoscopic partial nephrectomy. TISSEEL was used in group 1 (n 5 75), and sutured bolsters were used in group 2, in which injury to the collecting system or renal sinus was confirmed intraoperatively sutured surgical bolster is recommended by the authors in laparoscopic partial nephrectomy when intraoperative injury to renal sinus or collecting system is known, the study is confounded by the differences in tumor size and use of other adjuncts. In a study designed to explore whether fibrin sealants impact negatively on outcomes in robotassisted partial nephrectomy, Cohen and colleagues14 assessed 114 consecutive patients. EVICEL Fibrin Sealant (Ethicon, Somerville, NJ) fibrin sealant was used in the first 74 patients during renorrhaphy, and the other 40 patients had renorrhaphy without the use of a hemostatic agent. Multivariable logistic regression showed no significant predictive value of omission of hemostatic agents for perioperative outcomes (P . .05). In another study, Arnoux and coworkers15 compared perioperative outcomes in a hemostatic agents group (91 cases; 69.5%) with a conventional surgical hemostasis group (40 cases). The authors found no difference between the two groups with regard to surgical complications, transfusions, conversion to radical nephrectomy, or hospital stay. Hemostatic agents may be used to avoid clamping of the renal pedicle and therefore avoid ischemia altogether. Triaca and coworkers16 ® achieved effective control of parenchymal bleeding using a combination of Floseal and suture ligation without any vascular clamping in 37 of 43 open partial nephrectomy cases. Similarly, Finley and colleagues17 avoided hilar clamping in 14 of 15 patients undergoing laparoscopic wedge resection of nonhilar small renal lesions using a combination of a TISSEEL, harmonic scalpel, argon laser beam, and oxidized cellulose. Although the study was small and the role of TISSEEL is confounded by the use of other hemostatic devices, it demonstrates that, in a wellselected patient cohort, and with a range of laparoscopically delivered hemostatic devices available during surgery, it is possible to avoid hilar clamping during laparoscopic partial nephrectomy. Mele and associates18 undertook a prospective analysis of the use of TachoSil (Baxter Healthcare) in 3 pediatric patients with Wilms tumor (synchronous bilateral tumor in one) undergoing nephron-sparing surgery.18 All procedures were performed without hilar clamping, drainage, or stent placement, and none of the patients required blood transfusion. Small perirenal fluid collections were documented postoperatively, and all spontaneously resolved within 4 weeks of surgery. The authors concluded that, in children undergoing nephronsparing surgery, TachoSil is effective and safe for controlling mild to moderate bleeding, and also facilitates sealing and wound dressing. The safety of hemostatic sealants in laparoscopic nephrectomy without hilar clamping was further substantiated in another case series of small peripheral tumors in which clamp-free tumor excision was achieved in 44% (20/44) of cases. In all successful cases, Floseal was the sole hemostatic agent aside from the harmonic scalpel used ® 154 • Vol. 17 No. 3 • 2015 • Reviews in Urology 4004170006_RIU0673.indd 154 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice for dissection. Two patients had postoperative hemorrhage requiring intervention, and two cases required prolonged stent insertion for urinary extravasation. The authors, however, emphasized the reproducibility of this technique, as the outcomes were not significantly different among three experienced surgeons.19 Intraoperative blood pressure is an important factor that may influence postoperative outcome. Johnston and associates20 compared the efficacy of different hemostatic agents in 70 porcine partial nephrectomies at an elevated systolic blood pressure. Most agents were found to be effective for small resections at a systolic blood pressure of 100 mm Hg. However, only the combination of sutured bolster and Floseal was consistently effective with an elevated systolic blood pressure of 200 mm Hg. Rouach and colleagues21 also conducted a similar but randomized study in hypertensive pigs to compare different hemostatic agents with conventional suturing in achieving hemostasis and collecting system repair. The authors found that thrombin/gelatin granules decreased warm ischemia time and controlled bleeding as effectively as sutures, but suturing was most effective in closing an opened collecting system. Interestingly, the area of tissue necrosis around the wound was found to be smaller when no suturing was performed.21 A study comparing two nonrandomized cohorts of 32 patients with standard suture closure and 24 patients with closure using tissue sealants (BioGlue Surgical Adhesive; CryoLife, Kennesaw, GA and COSEAL Surgical Sealant; Baxter Healthcare) found a significantly better postoperative renal function using tissue sealant, with average renal function loss of 11.49%, ® compared with 20.36% when suturing was used (P 5 .02).22 The popularity of hemostatic agents in laparoscopic partial nephrectomy is shown in recent multi-institutional surveys across the United States and Europe.23,24 This showed routine use of a heterogeneous range of hemostatic agents, and overall transfusion (2.7%) and a wide-bore nephrostomy tube.27 Although risks of complications requiring intervention are small, patients require hospital admission for postoperative observation after removal of the nephrostomy tube. A pioneering study conducted by Pfab and coworkers28 explored the feasibility of using collagen-fibrin adhesive sealant to achieve hemo- A pioneering study … explored the feasibility of using collagenfibrin adhesive sealant to achieve hemostasis along the renal parenchymal tract, enabling the insertion of smaller nephrostomy tubes. urinary leakage (1.9%) rates were low. More recently, Minervini and colleagues25 describe how, in a multicenter study, they found that topical hemostatic agents were used in over 92% (n 5 943) of open or laparoscopic nephron-sparing surgical cases. Naitoh and associates26 recently described a surgical glue derived from food additives which offers an advantage over biologic agents due to reduced infection risk, superior self-degradability, and lower cost. Using animal partial nephrectomy models, they showed a significant reduction in blood loss when compared with fibrin glue. Demonstration of the true advantage of hemostatic agents and sealants in partial nephrectomy, however, requires a randomizedcontrolled study to investigate postsurgical outcomes. Percutaneous Nephrolithotomy Percutaneous nephrolithotomy (PCNL) differs from other surgical procedures of the kidney in that hemostatic adjuncts are not routinely applied to the kidney. Control of bleeding relies on tamponade achieved intraoperatively through insertion of serial dilators and postoperatively through stasis along the renal parenchymal tract, enabling the insertion of smaller nephrostomy tubes. The authors concluded that the fibrin glue was useful in reducing hemorrhage from the tract and obviated the use of large-bore nephrostomy tubes postoperatively. More recent studies have assessed the safety of completely tubeless PCNLs using hemostatic agents that are applied inside the parenchymal tract. An observational study compared the outcomes between patients with primary closure of tract using fibrin glue (TISSEEL; n 5 20) and a control group receiving the nephrostomy tube (n 5 23).29 Results showed no significant difference in postoperative hematocrit, pain, infection, or urinary leakage rates. The authors concluded that the use of fibrin glue is safe in tubeless PCNL. Another observational study compared outcomes between 17 TISSEEL-sealed tubeless PCNL cases and 25 PCNL cases with nephrostomy.30 There was no difference in bleeding or urine leakage rates, and the patients who received tubeless PCNL had shorter hospital stays and required less postoperative analgesia. Nagele and colleagues31 reported the tractsealing time of Floseal ranged from 2 to 5 minutes (n 5 11). Another randomized control trial compared Vol. 17 No. 3 • 2015 • Reviews in Urology • 155 4004170006_RIU0673.indd 155 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice continued a group that underwent TachoSil sealed tubeless PCNL (n 5 49) with a control group that received nephrostomy tubes (n 5 47).32 It showed a significant reduction in the urinary leakage rate and hospital stay, with no difference in analgesic requirement or pain scores. A large retrospective case series of 107 patients who underwent tubeless PCNL with hemostatic agents also found it to be associated with reduced hospital stay, though the authors acknowledged the limitations of this study.33 Outcomes in the above studies are mirrored in a systematic review and meta-analysis of randomized studies comparing tubeless PCNL versus PCNL with nephrostomy, with the exclusion of studies using sealants.34 The study found the tubeless procedure to be associated with reduced hospital stay and urinary leakage rates, with no detectable difference in postoperative hematocrit or transfusion rates. Postoperative pain was reduced in 5 of 6 studies, although heterogeneity prevented a meta-analysis. These findings suggested that the lack of nephrostomy tube alone is sufficient to explain the improved outcomes post PCNL. Further studies, however, explored the role of hemostatic agents in tubeless PCNL. A pro- Another randomized controlled trial of tubeless PCNL with or without the use of SPONGOSTAN™ Absorbable Haemostatic Gelatin Sponge (Ethicon), a gelatin tissue hemostatic agent, showed that application of sealant resulted in less postoperative pain and lower urinary extravasation rates, and also shorter hospital stay, without a detectable difference in blood loss.36 Not all studies share the same trend, however, as another randomized study of 20 patients undergoing PCNL with or without Surgicel ® absorbable hemostat (oxidized regenerated cellulose) (Ethicon) showed no significant difference in urinary extravasation rates.37 A recent randomized trial of patients undergoing PCNL compared three methods: tubeless PCNL with Floseal (n 5 10), tubeless PCNL with a fascial stitch technique (n 5 10), or PCNL with a Cope loop nephrostomy tube (n 5 11).38 The only significant outcome was the 1-week postoperative pain evaluated by the visual analogue scale, which was highest in the Floseal group, although as the authors suggest, the numbers in each group were too small to draw any accurate conclusion. One major concern remaining in the use of hemostatic agents and sealants in PCNL is the risk of Another randomized controlled trial of tubeless PCNL with or without the use of Spongostan™ (Ethicon), a gelatin tissue hemostatic agent, showed that application of sealant resulted in less postoperative pain and lower urinary extravasation rates, and also shorter hospital stay, without a detectable difference in blood loss. spective, randomized controlled trial comparing TISSEEL application (n 5 32) to no TISSEEL (n 5 31) in tubeless PCNL revealed that the use of sealant reduced postoperative pain and urinary extravasation rates, although difference in hospital stay and blood loss did not reach significance.35 urinary obstruction due to inadvertent sealing of the upper tracts. The safety of these agents in relation to the collecting system can be obtained from the experiments using different sealants in the porcine urinary collecting system. Hemostatic agents, when injected into the collecting system or ureter, caused significant obstruction, which did not resolve over a period of 5 days.39 The authors recommended the use of an occlusion balloon catheter to prevent spillage of such agents into the collecting system when used for tract sealing. Ways to maintain the patency of the upper urinary tract include the use of an occlusion balloon during sealant injection,40 or insertion of an antegrade stent,31 although the problem of sealant colic does not appear as a reported complication in any published trial. Pyeloplasty Although tissue sealants may be useful during pyeloplasty for pelviureteric anastomosis, few studies have addressed this potential in the clinical setting. One study investigated the preclinical efficacy of tissue glues in a porcine pyeloplasty model, comparing three different methods of tissue sealing.41 Fibrin glue was found to be superior to gelatin/resorcinol/formaldehyde glue and laser tissue welding when leak pressures and operating times were evaluated, and even withstood higher leak pressures than the conventional suturing techniques. The authors subsequently applied the technique in nine patients undergoing retroperitoneal laparoscopic dismembered pyeloplasty.42 Although stay sutures were used to oppose the urothelium and therefore the procedure was not totally suture-free, results showed shorter operative time and postoperative hospital stay, and less analgesia requirement than historical sutured control subjects, and showed satisfactory upper tract drainage as assessed by diuretic renography after 3 months. The efficacy of fibrin glue was further investigated in a larger porcine study comparing fibrin glued, laser-welded, or sutured anastomosis in pyeloplasty.43 Their findings, however, did not support the 156 • Vol. 17 No. 3 • 2015 • Reviews in Urology 4004170006_RIU0673.indd 156 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice previous benefits of glued anastomosis, showing urinoma formation in 4, and ureteric obstruction in 2 of 7 animals, and overall showed no benefit over sutured pyeloplasty. Borges and associates44 describe the use of a fibrin sealant in a coagulum pyelolithotomy, which can be used in the classic or robotic laparoscopic transperitoneal dismembered ureteropyeloplasty. They noted that the procedure results in reduced incidence of incomplete stone removal.44 Despite some encouraging results in a small case series, no subsequent studies have investigated the efficacy of tissue sealants in pyeloplasty in the clinical setting. Renal Trauma The use of hemostatic agents in renal trauma may improve outcomes by minimizing blood loss, preventing nephrectomy, or replacing coagulating hemostatic devices such as diathermy, which can damage surrounding parenchymal tissue. A porcine randomized study of artificially inflicted grade 4 renal injuries showed intraoperative repair using gelatin matrix (Floseal) to be superior over sutured gelatin sponge bolsters in reducing intraoperative blood loss and time to achieve hemostasis.45 A similar randomized porcine renal injury study comparing four different methods of repair showed repair by fibrin sealants to be superior over capsular suturing in reducing blood loss and time to hemostasis.46 No clinical studies have examined the role of hemostatic agents in renal trauma, mainly due to the emergency nature of these cases. Other Applications of Tissue Sealants in Urology Diverse use of tissue glues has been reported in simple retropubic prostatectomy,47 radical retropubic prostatectomy,48 surgery for Fournier gangrene,49 and for closure of urinary fistulas of different etiologies.50 Promising initial experience has been reported in patients with complex urethral stricture disease who underwent penile urethral reconstruction.51 The fibrin sealant group (n 5 18) enabled earlier catheter removal and wound healing compared with historic control subjects (n 5 25). Michael and colleagues52 described the successful treatment of unremitting gross hematuria following laparoscopic radical nephrectomy, with instillation of a fibrin sealant. In a single case review, Omar and associates53 reported the successful endoscopic delivery of cyanoacrylate and lipidol sealant in the treatment of urethrocutaneous fistula, with spontaneous healing of the opening on the skin a week later. Finally, in another single case study, Chao and coworkers54 described the successful use of TISSEEL fibrin sealant for the management of unremitting gross hematuria due to renal arteriopelvic fistula following PCNL. The authors suggest that fibrin sealants may be used as an adjunct to renal angiography and embolization when the source of bleeding cannot be accurately identified using traditional imaging modalities. which poses a challenge in performing a combined analysis. There is also a paucity of large welldesigned randomized controlled studies in the field, without which firm conclusions cannot be drawn. Success stories, however, have been reported in a small case series, and for the majority of cases, it remains for this hypothesis to be examined in larger studies. Although no robust grade 1A evidence yet exists to support the routine use of hemostatic agents in any urologic surgery, the message is clear that this will be achieved sooner than later. References 1. 2. 3. 4. 5. 6. 7. 8. 9. Conclusions Choosing the optimal method of hemostasis for each surgical technique may minimize perioperative blood loss, improve tissue viability, and prevent complications. Hemostatic agents and tissue sealants are one of many options to achieve effective hemostasis and tissue sealing in urologic surgery. One major problem is the heterogeneity in the previous studies, using a variety of surgical techniques and hemostatic agents, 10. 11. 12. 13. 14. 15. Carless PA, Henry DA, Anthony DM. Fibrin sealant use for minimizing peri-operative allogeneic blood transfusion. Cochrane Database Syst Rev. 2003;(2):CD004171. Spotnitz WD, Burks S. State-of-the-art review: hemostats, sealants, and adhesives II: update as well as how and when to use the components of the surgical toolbox. Clin Appl Thromb Hemost. 2010;16:497-514. Jemal A, Bray F, Center MM. et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90. Novick AC. 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Ploussard G, Haddad R, Loutochin O, et al. A combination of hemostatic agents may safely replace deep medullary suture during laparoscopic partial nephrectomy in a pig model. J Urol. 2015;193:318-324. 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(6 Pt 1):2446-2550. Pruthi, RS, Chun J, Richman M. The use of a fibrin tissue sealant during laparoscopic partial nephrectomy. BJU Int. 2004;93:813-817. Johnston WK 3rd, Montgomery JS, Seifman BD, et al. Fibrin glue v sutured bolster: lessons learned during 100 laparoscopic partial nephrectomies. J Urol. 2005;174:47-52. Cohen J, Jayram G, Mullins JK, et al. Do fibrin sealants impact negative outcomes after robot-assisted partial nephrectomy? J Endourol. 2013;27:1236-1239. Arnoux V, Descotes JL, Fiard G, et al. The use of haemostatic agent: impact on perioperative outcomes Vol. 17 No. 3 • 2015 • Reviews in Urology • 157 4004170006_RIU0673.indd 157 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice continued 16. 17. 18. 19. 20. 21. 22. 23. of partial nephrectomy [Article in French]. Prog Urol. 2013;23:317-322. Triaca V, Zagha RM, Libertino JA. Does thrombin sealant allow nephron-sparing surgery with no renal artery occlusion? A description of technique and initial results. BJU Int. 2005;95:1273-1275. Finley DS, Lee DI, Eichel L, et al. Fibrin glue-oxidized cellulose sandwich for laparoscopic wedge resection of small renal lesions. J Urol. 2005;173:1477-1481. Mele E, Ceccanti S, Schiavetti A, et al. The use of Tachosil as hemostatic sealant in nephron sparing surgery for Wilms tumor: preliminary observations. J Pediatr Surg. 2013;48:689-694. Wille AH, Tüllmann M, Roigas J, et al. Laparoscopic partial nephrectomy in renal cell cancer– results and reproducibility by different surgeons in a high volume laparoscopic center. Eur Urol. 2006;49: 337-342. Johnston WK 3rd, Kelel KM, Hollenbeck BK, et al. Acute integrity of closure for partial nephrectomy: comparison of 7 agents in a hypertensive porcine model. J Urol. 2006;175:2307-2311. Rouach Y, Delongchamps NB, Patey N, et al. Suture or hemostatic agent during laparoscopic partial nephrectomy? A randomized study using a hypertensive porcine model. Urology. 2009;73:172-177. Hidas G, Lupinsky L, Kastin A, et al. Functional significance of using tissue adhesive substance in nephron-sparing surgery: assessment by quantitative SPECT of 99m Tc-Dimercaptosuccinic acid scintigraphy. Eur Urol. 2007;52:785-789. Breda A, Stepanian SV, Lam JS, et al. Use of haemostatic agents and glues during laparoscopic partial nephrectomy: a multi-institutional survey from the United States and Europe of 1347 cases. 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Eden CG, Coptcoat MJ. Assessment of alternative tissue approximation techniques for laparoscopy. Br J Urol. 1996;78:234-242. Eden CG, Sultana SR, Murray KH, Carruthers RK. Extraperitoneal laparoscopic dismembered fibringlued pyeloplasty: medium-term results. Br J Urol. 1997;80:382-389. MAin PoinTs • The manner in which hemostasis and tissue adhesion is achieved intraoperatively is critical to improving the outcomes of urologic surgery. The ideal hemostatic agent must achieve instant closure of blood vessels without damage to surrounding tissues, is immunologically inert, and must maintain the tissue seal until vascular obliteration and tissue healing occurs. These agents can be broadly classified into topical hemostatic agents, tissue sealants, and tissue adhesives. • Partial nephrectomy is a common urologic procedure performed for small renal tumors in patients with preexisting renal failure or solitary kidney, when preservation of nephrons is paramount. Reducing the ischemia time arising from clamping of the renal hilum is an important aim during surgery, as longer ischemia times are thought to be associated with longer renal function recovery times. Topical hemostatic agents are feasible alternatives to traditional methods of hemostasis, as they can easily be applied through laparoscopic port sites. • Percutaneous nephrolithotomy differs from other surgical procedures of the kidney in that hemostatic adjuncts are not routinely applied to the kidney; control of bleeding relies on tamponade achieved intraoperatively through insertion of serial dilators and postoperatively through a wide-bore nephrostomy tube. Fibrin glue has been useful in reducing hemorrhage from the tract and obviates the use of large-bore nephrostomy tubes postoperatively. • The use of hemostatic agents in renal trauma may improve outcomes by minimizing blood loss, preventing nephrectomy, or by replacing coagulating hemostatic devices such as diathermy, which can damage surrounding parenchymal tissue. • Diverse use of tissue glues has also been reported in simple retropubic prostatectomy, radical retropubic prostatectomy, surgery for Fournier gangrene, and for closure of urinary fistulas. 158 • Vol. 17 No. 3 • 2015 • Reviews in Urology 4004170006_RIU0673.indd 158 19/10/15 12:42 pm Current Status of Hemostatic Agents and Sealants in Urologic Surgical Practice 43. 44. 45. 46. 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(3 Pt 2):1106-1110. Borges R, Azinhais P, Retroz E, et al. 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J Urol. 2005;174:2239-2243. 51. 52. 53. 54. Hick EJ, Morey AF. Initial experience with fibrin sealant in pendulous urethral reconstruction. Is early catheter removal possible? J Urol. 2004;171:1547-1549. Michael A, Sheridan-Jonah A, Kovac JR, et al. A novel endoscopic treatment for ureteric remnant hemorrhage post laparoscopic radical nephrectomy. Scand J Urol. 2013;47:244-247. Omar M, Abdulwahab-Ahmed A, El Mahdey Ael D. Endoscopic management of a chronic ureterocutaneous fistula using cyanoacrylic glue. Cent European J Urol. 2014;67:430-432. Chao D, Abdulla AN, Kim S, et al. A novel endoscopic treatment for renal arteriopelvic fistula post-percutaneous nephrolithotomy (PCNL). Int Braz J Urol. 2014;40:568-573. Vol. 17 No. 3 • 2015 • Reviews in Urology • 159 4004170006_RIU0673.indd 159 19/10/15 12:42 pm