Management of surgical hemostasis: topical agents

Intraoperative control of bleeding during any surgical procedure is vital for achieving a positive patient outcome. Hemostasis can be achieved through practical and effective systemic or topical approaches. A variety of hemostatic methods can be employed, ranging from simple manual pressure application with one finger to electrical tissue cauterization, systemic administration of blood products, and systemic administration or topical application of procoagulation agents. The key to surgical success is critically dependent on knowledgeable use of a method appropriate for the level of bleeding experienced by the patient. Topical agents can be effective as adjuncts to aid in hemostasis when bleeding is not controllable with pressure application, vessel ligation, or electrocautery. Such adjunctive hemostatic treatments include topical gelatins, collagens, oxidized celluloses, thrombin and fibrin sealants, synthetic glues, and glutaraldehyde-based glues. As with the use of systemically delivered hemostatic agents, topical treatments also carry risks with their use, and their efficacy has not been extensively studied in large randomized, placebo-controlled prospective studies. The effective use of topical agents is highly dependent on the surgeon's experience or preference and their availability in the surgical setting. In this article, we review the currently available topical hemostatic agents, compare their efficacy, and give general recommendations for their use in the operating room.     

Comparison of a new fibrin sealant with standard topical hemostatic agents

BACKGROUND: Bleeding following liver resection continues to be a significant morbidity of the procedure. Fibrin sealants represent an improvement over conventional topical hemostatic agents, because they contain components that actively form clot. However, most available agents contain nonhuman protein, which represents an immunologic risk. HYPOTHESIS: An investigational surgical fibrin sealant (Crosseal; American Red Cross, Washington, DC) composed of human clottable proteins and human thrombin is more effective than standard topical hemostatic agents in reducing the time required to achieve hemostasis after liver resection. DESIGN: Prospective, randomized, controlled trial. SETTING: Fifteen major referral centers in the United States and the United Kingdom. METHODS: After liver resection using standard surgical techniques, 121 patients seen between May 1999 and May 2000 were randomized to treatment with a 2-component fibrin sealant (n=58) or to standard topical hemostatic agents, used singly or in combination (n=63). Up to 10 mL of Crosseal was administered by a spray applicator, as recommended by the manufacturer, whereas agents used in the control group were applied according to their instructions for use. MAIN OUTCOME MEASURES: The primary outcome measured was time to hemostasis. Secondary outcomes measured included blood loss between application of the hemostatic agent and closure of the abdomen, duration of postoperative biliary drainage, and the occurrence of complications, defined a priori as reoperation for any reason, development of abdominal fluid collections, or bilious appearance of drained fluid for at least 1 day postoperatively. RESULTS: The mean time to hemostasis was 282 seconds with Crosseal, compared with 468 seconds with standard agents (2-sided; P =.06), for the 116 efficacy-evaluable patients. Hemostasis was achieved within 10 minutes in 53 patients (91.4%) treated with the study fibrin sealant and in 44 control patients (69.8%) (2-sided; P =.003). Intraoperative blood loss was similar in the 2 groups. In the Crosseal group, the percentage of patients developing postoperative complications was 17.2%, compared with 36.5% in the control group (2-sided; P =.02). CONCLUSIONS: Compared with the use of standard topical hemostatic agents, Crosseal fibrin sealant significantly reduced the time to achieve hemostasis following liver resection. Patients treated with the new fibrin sealant also experienced significantly fewer postoperative complications.     

Elastomeric surgical sealant for hemostasis of cardiovascular anastomosis under full heparinization.

PURPOSE: We developed a novel surgical sealant, a viscous diisocyanated prepolymer, applicable to arterial hemostasis. The purpose of this study is to evaluate hemostatic effect of this surgical sealant under heparinized conditions. METHODS: The effectiveness of this sealant was verified by applying it to the end-to-end anastomosis of canine carotid arteries. Five mongrel dogs were used. After a complete heparinization, the carotid arteries were clamped, divided, and end-to-end anastomoses were performed with four simple interrupted sutures. The sealant was coated on the anastomosis. After 5 min the clamps were removed and the hemostatic effect was evaluated. Three dogs were immediately subjected to macroscopic evaluation. Two dogs were subjected to angiography after 3 months and 16 months, respectively. RESULTS: No bleeding occurred in any of the anastomoses immediately after the removal of the clamp. Macroscopic finding revealed no leakage of the sealant into the lumen. Carotid angiography revealed patent anastomoses without stenosis. CONCLUSION: A novel surgical sealant exhibited rapid and potent hemostatic effect on a moisturized tissue under full heparinization.     

Acute intraoperative malfunction of aortic valve due to surgical glue

The use of surgical glues in aortic surgery has gained wide popularity due to their hemostatic and tissue reinforcing properties. Reports of acute complications associated with application of glue are rare. We report the case of a 52-year-old fragile, steroid-dependent woman who developed acute intraoperative dysfunction of an aortic prosthetic valve due to use of BioGlue surgical adhesive. A brief literature review of the acute and long-term complications of the glue is presented.     

Combination of a liquid fibrin sealant with sheet‐type hemostatic agents: Experimental evaluation in partial nephrectomy animal model

Liquid fibrin sealants, together with sheet‐type hemostatic agents, have been used during partial nephrectomies to secure effective hemostasis at the suture site. Using animal kidneys, we investigated which hemostatic agent might adhere most effectively to the renal tissue and serve best as a bolster. Liquid fibrin sealant alone, or in combination with a sheet‐type hemostat, such as collagen, gelatin or oxidized‐cellulose hemostat, was applied to the cut surface of the kidney of anesthetized rabbits, and the differences in the degree of adherence to the kidney and resultant hemostatic efficacy were evaluated. Histological analyses were also carried out to compare the degree of adherence of each of the aforementioned hemostats to the kidney tissue. Fibrin sealant plus the collagen or gelatin hemostat was found to have a stronger hemostatic effect than fibrin sealant applied alone or fibrin sealant plus oxidized‐cellulose hemostat. The histological investigation showed that the fibrin sealant adhered well to kidney tissue when it was applied with the collagen or gelatin hemostat, showing the advantage of combining these two materials for achieving effective hemostasis. Fibrin sealant used in combination with the collagen or gelatin hemostat was the most suitable for obtaining a reinforced hemostatic effect at the suture site in a partial nephrectomy animal model.     

Fibrin sealant tissue adhesive--review and update

The field of surgical tissue adhesives is rapidly developing, with multiple products now available. Fibrin sealant, the first widely available tissue adhesive, continues to be used in traditional as well as in new and creative ways. The product is now fully mature as a hemostatic agent in cardiac, liver, and spleen surgery. It is also useful as a sealant in a variety of clinical applications, including procedures such as colonic anastomosis, as well as in seroma prevention following soft tissue dissection. Newer uses such as reduced suture vascular and intestinal anastomosis, fistula closure, surgery in patients with hemophilia, and laparoscopic/endoscopic procedures are being studied in both laboratory and clinical settings. The most recent additions to the capabilities of fibrin sealant include the use of this tissue adhesive as a slow-release drug delivery system and as a substrate for cellular growth and tissue engineering. This article will review the basis of fibrin sealant effectiveness and will also cover the recent developments in the rapidly evolving employment of this material.     

Hemostatic effect of Vivostat patient-derived fibrin sealant on split-thickness skin graft donor sites

Topical hemostatic agents are used frequently to control bleeding of skin graft donor sites. In this study, the hemostatic properties of Vivostat (Vivolution A/S, Birker?d, Denmark) patient-derived fibrin sealant were compared with a control group of spray thrombin solution, which is considered an industry standard for topical hemostasis. Treatments were applied simultaneously to two randomly chosen halves of a single split-thickness single donor site in patients in five United States surgical centers. The time to achieve satisfactory hemostasis (< or =10 min) was estimated on each half of the wound as the time at which active bleeding had stopped and the wound was suitable for application of a surgical dressing. The time to hemostasis of wounds treated with Vivostat (Vivolution A/S) patient-derived sealant was significantly shorter in comparison with wounds treated with thrombin solution (medians: Vivostat, 31 seconds; thrombin, 58 seconds; p=0.0012). No abnormalities in wound healing were reported for either treatment site 1 week after the operation. Vivostat (Vivolution A/S) sealant is a more rapidly effective topical hemostatic agent than thrombin on split-thickness skin graft donor sites.     

Thermal injury resulting from application of a granular mineral hemostatic agent

BACKGROUND: Uncontrolled hemorrhage accounts for the majority of deaths in combat. Effective topical hemostatic agents suitable for use on the battlefield may be valuable in controlling hemorrhage until definitive surgical intervention is possible. In an effort to identify a hemostatic agent suitable for battlefield use, we evaluated several potential hemostatic agents in a swine injury model and noted thermal injury to tissues with a granular mineral hemostatic agent (QuikClot). METHODS: Anesthetized swine were maintained with a mean arterial pressure in excess of 60 mm Hg. Cutaneous, muscular, hepatic, splenic, venous, and arterial wounds were created in a standardized fashion. Topical hemostatic agents were immediately applied to the wounds and the amount of bleeding and time to hemostasis were noted. RESULTS: The results reported here are part of a larger study in which a variety of hemostatic agents were evaluated. Only the findings related to the granular mineral hemostatic agent are discussed here. Application of the agent resulted in elevated tissue surface temperatures in excess of 95 degrees C and internal tissue temperatures exceeding 50 degrees C, 3 mm deep to the bleeding surface. Necrosis of fat and muscle were noted as well as full and partial thickness cutaneous burns. CONCLUSIONS: Topical administration of a granular mineral hemostatic agent to a variety of wounds in an experimental swine model resulted in thermal tissue injury and necrosis. Suggestions for reducing the extent of injury with this product are offered.     

Tissue adhesives in endosurgery

Usage of tissue adhesives/glues for tissue approximation and hemostasis is increasing as the related technology advances. There is no accepted classification, but surgical adhesives fall into 3 main categories: biological, synthetic, and genetically engineered polymer protein glues. Nonresorbable glues should be confined only to surface application, such as closure of the wound edges. Adhesives for internal use, including hemostasis, tissue edge approximation, mesh hernioplasties, sealing of cerebrospinal fluid (CSF) fluid and intestinal leaks, and anastomoses, should be biocompatible and resorbable. In time, tissue glues and soldering will likely replace, in whole or in part, the use of sutures and staples for a variety of tissue approximation surgical procedures.     

Fibrin solutions to control hemorrhage in the trauma patient

Fibrin sealant has been used by a variety of surgical subspecialties as a biological adhesive, sealant, and hemostatic agent. The advantages of these fibrin solutions make them ideal adjunctive hemostatic agents for patients with intra-abdominal solid organ injury. Control of hemorrhage from large stellate wounds of the liver and splenic salvage has been documented in the literature by surgeons from Europe and the United States. Due to the unavailability of a commercial product, surgeons in the United States have had to rely on blood bank-produced fibrin sealant. The purpose of this review is to describe research directed towards developing and evaluating fibrin solutions, both commercial and blood bank-produced, for hemostasis of injuries to the liver and spleen.     

Current applications of fibrin sealant in urologic surgery

Biosurgical preparations designed to promote surgical hemostasis and tissue adhesion are being increasingly employed across all surgical disciplines. Fibrin sealant is the most widely studied and utilized biosurgical adjunct in urology. Complex reconstructive, oncologic, and laparoscopic genitourinary procedures are those most appropriate for sealant use. This article details the diverse urologic applications of fibrin sealant in the management of genitourinary injuries, surgery, and complications.     

New developments in the use of fibrin sealant: a surgeon's perspective

Fibrin sealant, a surgical tissue adhesive, has gained widespread use for its ability to achieve three major clinical goals: reducing hemorrhage, increasing tissue adherence, and allowing drug delivery. The object of this state-of-the-art review is to clarify the most recent developments in this field from a surgical perspective. The areas of greatest interest and progress relating to surgical uses for fibrin sealant--specifically, new methods of sealant production, new experimental or clinical uses, and new potential complications--are explored in this review.     

Möglichkeiten der lokalen und systemischen Blutstillung bei chirurgischen Eingriffen

Surgery inevitably leads to bleeding, and hemostasis aims at reducing the amount of blood loss and the need for transfusion as well as preventing rebleeding, hematoma formation, and the need for repeat surgery. Various locally applicable agents are in use including bone wax, gelatin, collagen, oxidized regenerated cellulose, fibrin sealant glues, and synthetic glues. Some evidence from randomized controlled trials (RCT) exists regarding the use of fibrin sealants on their own or combined with collagen fleece. Systemic hemostasis may be achieved with lysine analogs such as epsilon-aminocaproic acid or tranexamic acid and aprotinin, which are inhibitors of fibrinolysis. There is much albeit sometimes conflicting evidence from RCT regarding the use of these substances in surgery. The role of recombinant activated factor VII in achieving systemic hemostasis is being investigated.     

Local and systemic hemostasis in surgery]

Surgery inevitably leads to bleeding, and hemostasis aims at reducing the amount of blood loss and the need for transfusion as well as preventing rebleeding, hematoma formation, and the need for repeat surgery. Various locally applicable agents are in use including bone wax, gelatin, collagen, oxidized regenerated cellulose, fibrin sealant glues, and synthetic glues. Some evidence from randomized controlled trials (RCT) exists regarding the use of fibrin sealants on their own or combined with collagen fleece. Systemic hemostasis may be achieved with lysine analogs such as epsilon-aminocaproic acid or tranexamic acid and aprotinin, which are inhibitors of fibrinolysis. There is much albeit sometimes conflicting evidence from RCT regarding the use of these substances in surgery. The role of recombinant activated factor VII in achieving systemic hemostasis is being investigated.     

Polyethylene glycol based synthetic sealants: potential uses in cardiac surgery

Focalseal is a polyethylene glycol based synthetic hydrogel. It is FDA approved as a sealant to limit airleak following pulmonary resection. In preclinical use, this type of sealant has also been shown to be effective as a hemostatic adjunct to prevent anastomotic bleeding and to seal other types of closure such as the dura, pancreatic stump, or open wounds. The sealant has two components, a primer and a sealant, and is applied in two steps and then polymerized by the application of a blue-green light (Fig. 1) (Genzyme Biosurgery, Inc. Cambridge, MA). The sealant does not bond covalently to tissue and is degraded by hydrolysis. This kind of sealant is flexible and nontoxic and has many intriguing possible applications as well as some mechanical properties that are essential to understand for safe use.     

Hemostatic agents and tissue glues in urologic injuries and wound healing

Biosurgical preparations designed to promote surgical hemostasis and tissue adhesion are now available to the urologist and are increasingly being used across all surgical disciplines. Fibrin sealant and gelatin thrombin matrix are the two most widely used bio-surgical adjuncts in urology. Complex reconstructive, oncologic, and laparoscopic genitourinary procedures are those most appropriate for sealant use. This article details the diverse urologic applications of biosurgical products in the management of urologic injuries and the promotion of wound healing.     

Fibrin sealants in clinical practice

Fibrin sealants are used in a wide range of surgeries, primarily as hemostatic agents, but also to assist tissue sealing and wound healing. While all fibrin sealants contain fibrinogen and thrombin, they differ in their final composition. This affects the properties of the resulting fibrin clot and may influence their use in different surgical procedures. Sealants with high concentrations of fibrinogen tend to produce stronger clots, whereas those containing higher concentrations of thrombin form clots rapidly. This is essential when rapid hemostasis is required to stop blood loss (e.g. suturing of blood vessels). However, in situations that require careful adjustment of tissue (e.g. a skin flap) a slower clot formation is advantageous. Some sealants are supplemented with factor XIII and this may increase the tensile strength and stability of the clot and improve hemostasis. Antifibrinolytic agents (e.g. aprotinin and aminocaproic acid) increase the lifespan of the clot by inhibiting fibrinolysis. Fibrin sealants containing aprotinin may have an added advantage when used on surgical sites with naturally high concentrations of fibrinolytic agents. The physical properties of the fibrin sealants also vary. For example, the fibrinogen component is relatively viscous and requires a lot of force to inject it through a long catheter. Fibrin sealants with a fibrinogen component of low viscosity are easier to use than highly viscous solutions in surgical situations where the sealant is applied by a catheter. Until recently, the use of fibrin sealants in the USA has been limited to noncommercial products--'home-brews'. The fibrinogen concentration of these products can vary between preparations, with subsequent variation in the mechanical strength of the clot making handling difficult. The introduction of commercial sealants into the USA with consistent composition should reduce the varying performance of fibrin sealants, although autologous and point-of-use prepared sealants may still vary. Consistency of performance is expected to result in an increased use of fibrin sealants both in established and novel fields of surgery.     

Fibrin sealant for the management of genitourinary injuries,fistulas and surgical complications

PURPOSE: We report our preliminary experience with the use of fibrin sealant to manage iatrogenic urinary tract injuries, complex urinary fistulas, and urological surgical complications. MATERIALS AND METHODS: Topical fibrin sealant was used in 19 patients for iatrogenic urinary tract injury during gynecological or general surgical procedures (7), complex urinary fistulas (5) or urological surgical complications (7). RESULTS: Successful resolution of the injury, fistula or complication was attained after a single application of fibrin sealant in the 18 patients (94.7%) in whom a direct injection technique was used. The only failure (formation of a vesicovaginal fistula) occurred with the air driven sprayed sealant delivery technique after sutured closure of iatrogenic cystotomy during vaginal hysterectomy. CONCLUSIONS: Liquid fibrin sealant appears to be safe and prudent for use in urological "damage control" from trauma, fistulas or surgical complications. Direct injection over a sutured urinary anastomosis appears to be highly effective in preventing urinary drainage. Additional study is needed to define further the role and best use of tissue adhesives in urology.     

What happens to hemostatic agents in contact with urine? An in vitro study

BACKGROUND AND PURPOSE: As the indications for topical hemostatic agents increase in urology, the question arises: what happens to these agents when they enter the urinary collecting system? To answer this question, we performed a series of in-vitro experiments mixing three hemostatic agents with normal and sanguineous urine. MATERIALS AND METHODS: Four commercially available topical hemostatic products: oxidized regenerated cellulose (Surgicel; Ethicon, Somerville, NJ), fibrin sealant (Tisseel VH Kit; Baxter Health Care Corporation, Irvine, CA), gelatin matrix hemostatic sealant (FloSeal; Baxter Health Care), and polyethylene glycol (CoSeal; Cohesion Technologies, Palo Alto, CA) were studied. Human urine (10 mL) was added to samples of each substance; this was done in triplicate. The 12 sample tubes were then capped and placed on a tube shaker at slow speed and 37 degrees C. Observations regarding consistency of the material were made at 6, 12, 24, 48, 72, 96, and 120 hours (5 days). Gelatin matrix hemostatic sealant was further tested in urine with various amounts of blood or blood clot; observations were again recorded out to 5 days. RESULTS: Surgicel maintained its solid form when it initially came in contact with urine, but over a period of 5 days, it transformed into a mucoid substance with visible free-floating fibers. It did not dissolve completely in urine within 5 days. Gelatin matrix was immediately transformed by urine into a fine colloidal suspension that did not change over the 5 days of the study. Fibrin glue, after mixing of the two components (fibrinogen and thrombin) directly in the urine, and polyethylene glycol immediately formed a solid clot at the bottom of the test tube on contact with the urine. When the mixture of fibrin sealant was allowed to form for 15 minutes and then added to urine, it again maintained a solid form. After 72 hours, the fibrin glue became a semisolid gelatinous plug. On analysis at 5 days, the fibrin sealant clot had transformed into a cohesive mucoid gel, and the polyethylene glycol clot had not changed. The gelatin matrix hemostatic sealant, when in contact with blood or blood clot, appeared to either become part of a clot or to remain in a colloidal suspension. At 5 days, all clots had dissolved to fine particulate suspensions, and the gelatin matrix appeared as a fine suspension. CONCLUSION: Fibrin glue and oxidized regenerated cellulose maintain a solid form when initially placed in direct contact with urine and then assume a semisolid gelatinous state, which is still present at 5 days. Polyethylene glycol forms a solid clot initially and does not change after 5 days. Only hemostatic gelatin matrix remained as a fine particulate suspension in both normal and sanguineous urine. The implications of these findings with regard to sealing the renal parenchyma or small violations of the collecting system after percutaneous or laparoscopic surgery await in-vivo testing.     

Cyanoacrylate tissue sealant impairs tissue integration of macroporous mesh in experimental hernia repair

BACKGROUND: Tissue sealants have been proposed as an alternative to permanent fixation devices in hernia repair with the aim of reducing perforation-associated complications and chronic pain. Sealants can be divided into three main categories: synthetic glues (e.g., cyanoacrylate based), biologic products (e.g., fibrin sealant), and genetically engineered polymer protein glues. The beneficial effects of fibrin sealant have been reported in both experimental and clinical hernia repair. However, data on cyanoacrylate glues for mesh sealing are limited. METHODS: In 20 Sprague-Dawley rats, two hernia defects (1.5 cm in diameter) per animal were created bilaterally in the midline of the abdominal wall. The peritoneum was spared. The lesions were left untreated for 10 days to achieve a chronic condition. Defects then were covered with TI-Mesh xl (2 x 2 cm), which was glued with Glubran-II. The time points of sacrifice were 17 days, 28 days, and 3 months. At autopsy, meshes were biomechanically tested, and histology was performed. RESULTS: Tissue integration of the meshes was impaired at all time points by impenetrable glue plaques. At application sites, the elasticity of the abdominal wall was significantly reduced because of nonresorbed, rigid glue residues. CONCLUSIONS: Mesh fixation by Glubran-II impairs tissue integration, elicits inflammation, and unfavorably alters the biomechanics of macroporous mesh and the abdominal wall.