Overview of topical hemostatic agents and tissue adhesives

INTRODUCTION — Intraoperative bleeding is controlled using standard surgical techniques (eg, electrocautery, vessel ligation, suturing). Using these techniques, blood loss is minimal, with most routine, elective operations in patients with normal hemostasis. Topical hemostatic agents (physical agents, biologically active agents) and tissue adhesives are used as an adjunct or alternative to standard surgical techniques to manage bleeding from surgical surfaces, and are particularly useful for diffuse nonanatomic bleeding, bleeding associated with sensitive structures, and bleeding in patients with hemostatic abnormalities.

The mechanism of action, indications, and clinical application of the most common topical hemostatic agents and tissue adhesives used in surgery are reviewed here. Devices used to achieve surgical hemostasis through vascular control during dissection are discussed elsewhere. (See "Overview of electrosurgery" and "Instruments and devices used in laparoscopic surgery".)

HEMOSTATIC AGENTS — Topical hemostatic agents are used when surgical hemostasis is inadequate or impractical. The two main categories of topical hemostatic agents are physical agents, which promote hemostasis using a passive substrate, and biologically active agents, which enhance coagulation at the bleeding site (table 1). (See 'Physical agents' below and 'Biologically active agents' below.)

Indications for use — Topical hemostatic agents are primarily used for diffuse bleeding from:

●Peritoneal or pleural surfaces

●Cut surfaces of solid organs [1-3]

●Cut edges of bone

●Bleeding near nerves

●Bleeding near vital structures at risk for cautery-induced injury

●Bleeding from vascular structures or grafts due to suture holes (see 'Surgical scenarios' below)

●Nasal structures as nasal packing [4,5]

●Dental extraction sites [6]

Topical hemostatic agents can also be used for other purposes, including the management of:

●Air leak following lung resection [7]

●Eardrum perforation [8]

●Endoscopic control of gastrointestinal bleeding [9-11]

●Leakage prevention from colonic anastomoses following the reversal of temporary colostomies [12]

Contraindications — Topical hemostatic agents should not be used intravascularly, because they will cause thrombosis. Also, they should not be used in confined spaces where expansion of the product could lead to compression. (See 'Adverse effects and complications' below.)

Physical agents

Dry matrix — Dry matrix agents promote hemostasis through several effects. The matrix material provides a stimulus that activates platelets and the extrinsic pathway and provides a scaffold for thrombus deposition. The dry matrix also absorbs water, concentrates hemostatic factors at the site of bleeding, and tamponades bleeding vessels by exerting pressure. These agents are easy to use; however, they are less effective if bleeding is brisk.

The agent is applied to the site of bleeding, followed by gentle pressure with a surgical sponge. Care must be taken in removing the sponge because these agents generally adhere to the underlying tissue and will remove the clot that has formed if removed quickly. A useful technique for removal is wetting the sponge thoroughly and lifting the sponge from one edge, slowly rolling the sponge off the clotted area.

Oxidized regenerated cellulose — Oxidized regenerated cellulose (ORC) is a dry, absorbable sterile mesh (eg, Surgicel) that can be applied directly to an area of bleeding. A single-layer sheet is fully absorbed in approximately 14 days [13]. Results are optimal if bleeding is minimal (ie, oozing).

ORC is commonly used to control bleeding at vascular anastomotic sites, the cut surfaces of solid organs, and retroperitoneal or pelvic surfaces after lymphadenectomy. Because ORC is pliable, it can be rolled and passed easily through laparoscopic trocars [14,15].

In vitro studies have found that ORC has bactericidal activity against a wide range of gram-positive and gram-negative organisms because of its acidic pH [16,17]. The low pH also inhibits proteases and elastase, which may be beneficial in chronic wounds; however, this same property may inhibit its resorption [18]. Residual ORC is associated with infection and adhesion formation. In one study of 360 patients with postoperative pelvic abscess, unabsorbed ORC was identified as a risk factor, and in some cases un-resorbed ORC was found at laparotomy more than 12 months after it was placed [19].

Gelatin matrix — Gelatin (eg, Gelfoam, Surgifoam) is a hydrocolloid made from acid partial hydrolysis of porcine-derived collagen that is whipped into foam and then dried. It is available in sponge or powder form [20,21]. Gelatin sponge absorbs blood or fluid up to 40 times its weight, and it expands up to 200 percent in its dimensions [22].

The dry sponge form can be tailored to any shape, and although rigid when dry, the sponge is pliable after moistening and passes easily through laparoscopic ports. Once in place, pressure is applied for several minutes to achieve hemostasis. The sponge can be left in place and is completely absorbed after four to six weeks.

Because gelatin foam has a neutral pH, it does not inactivate thrombin, and thus, it is common practice to moisten it with topical thrombin to synergize the effects of these agents. The relative effectiveness of gelatin foam with or without thrombin has not been the subject of clinical trials. In a pig model of splenic laceration, gelatin foam without thrombin required two 20 second periods of finger pressure to stop breakthrough bleeding, while gelatin foam with thrombin needed only one 20 second period [23].

The disadvantages of gelatin include an increased incidence of infection, granuloma, and fibrosis formation and, similar to dry matrix product, the potential for disruption of the clot if the sponge is removed [13,20]. Although all brands of gelatin matrix are derived from porcine connective tissue, it is not considered to be antigenic.

Microporous polysaccharide spheres — Microporous polysaccharide spheres (MPS; eg, Arista) are derived from potato starch, which accelerates clot formation by acting as a molecular sieve to absorb water and concentrate platelets and blood proteins. MPS is available in powder form.

MPS is used by first applying pressure to the bleeding site with a dry surgical sponge for two minutes to achieve a relatively dry surface, then liberally applying the powder with the bellows applicator. Gentle pressure is reapplied with a fresh surgical sponge for one to two minutes until hemostasis is achieved.

The advantages of MPS include low cost, rapid absorption within 48 hours, and freedom from transmissible viruses or alloantigens. In addition, MPS does not act as a nidus for infection or cause foreign body reactions [24,25]. It is used in cosmetically sensitive areas such as face lifts and been approved for use in neurosurgery [26].

Microfibrillar collagen — Microfibrillar collagen (MC) is an absorbable acid salt obtained from bovine collagen (eg, Avitene). MC acts as a scaffold for clot formation and activates platelets. MC can be applied directly to the bleeding site as a powder [27,28], but foam sheet formulations (Avitene Ultrafoam) are available. MC is fully absorbed within three months. MC remains effective with heparinization but is less effective when platelet counts are below 20,000/mm³.

MC is indicated for use in neurosurgery and urology, and also for providing hemostasis in vascular surgery. A manufacturer-sponsored single-center trial (64 polytetrafluoroethylene [PTFE] arterial bypass graft anastomoses in 32 patients) found a significantly shorter time to hemostasis using microfibrillar collagen compared with oxidized, regenerated cellulose (125 versus 416 seconds) [29].

MC is contraindicated in blood scavenging systems because the fibers can pass through the filters, causing embolization and, potentially, disseminated intravascular coagulation.

Bone wax and putty — Blood oozing from the cut surface of medullary bone is a common feature of median sternotomy, orthopedic, and neurosurgery procedures. Agents placed into the cut surface to minimize bleeding are made of natural or synthetic substances.

●Bone wax – Bone wax, which is composed of beeswax, paraffin, and wax-softening agents, physically occludes bleeding vessels within bone to stop bleeding. When using bone wax, a minimal amount should be used, and it is rubbed across the surface of the bone surface without leaving a raised plug. Bone wax is inexpensive and effective but can lead to infection or granuloma formation, which can interfere with bone healing [30,31]. In one retrospective study in neurosurgical patients, the incidence of surgical site infection significantly decreased when bone wax was no longer used (14.2 versus 1.3 percent) [31].

●Ostene – Ostene is a wax-like compound of a water-soluble alkaline oxide copolymer that occludes bleeding vessels in bone like bone wax, but it does not persist in the wound as a foreign body. In animal studies comparing Ostene with bone wax, Ostene did not remain in the wound beyond three weeks, and bone healing was more pronounced in the Ostene group [32,33].

●Bone putty – A resorbable hemostatic bone putty (Hemasorb Plus) is comprised of granular hydroxyapatite/beta-tricalcium phosphate and water-soluble components that are fully synthetic and resorbable. It is available in moldable strips and in an applicator that does not require kneading.

External agents — In rescue or battlefield situations, external hemorrhage is generally controlled with direct pressure and standard dressings; however, when these are ineffective, external topical agents can be used as specialized dressings to temporize hemorrhage until definitive management is possible. A number of products have been used by the United States military to control external bleeding in the combat setting, and some have been extended for civilian use (table 1) [34-37]. In the operating room, externally applied agents should be removed under anesthesia just prior to prepping and draping unless there is a risk of severe, life-threatening hemorrhage upon removal of the dressing. In this situation, proximal vascular control should be obtained prior to removing the material.

Some of these agents have been tried for controlling bleeding during surgery, but their indications and effectiveness are not fully known at this time.

HemCon bandage — The HemCon bandage is a dressing composed of lyophilized chitosan, a biodegradable complex carbohydrate derived from chitin. Its hemostatic function is attributed to the strong adhesive properties of chitosan, which attaches firmly to wet tissues and seals bleeding vessels [34]. Successful use of this bandage as a hemostatic agent for prehospital combat casualties has been reported when standard methods were unsuccessful [36].

HemCon bandage has also been used in a civilian emergency medical services system when conventional treatment (ie, pressure and gauze dressings) failed to control external bleeding wounds, or for obvious arterial bleeding. Results included [38]:

●HemCon bandage controlled hemorrhage in 27 of 34 cases (79 percent), most often within three minutes of application.

●The bandage effectively controlled bleeding in 19 of the 25 cases in which direct pressure had initially failed.

●No adverse events or complications were reported. Proper training in the use of this bandage was considered essential as user error was a contributing factor in most of the documented failures.

ChitoFlex — ChitoFlex is a rolled version of chitosan in a different formulation than the HemCon bandage. It is very pliable and is designed to be packed into a wound tract [35].

QuikClot — QuikClot is a kaolin-based dressing. Kaolin is an inorganic product that activates factor XII of the coagulation cascade. Kaolin-based QuikClot products are available for a variety of applications for control of external as well as internal bleeding during surgery [39-41]. QuikClot in the form of a gauze or pad has been used in combat situations to control external bleeding [42].

The prior formulation of QuikClot was a zeolite-based granule with low (1%) moisture that, when placed on a bleeding wound, absorbed water and concentrated red cells, platelets, and clotting proteins at the injury site, thereby promoting rapid coagulation and arresting hemorrhage [34]. The reaction released significant amounts of heat, with the potential of causing thermal injury in some tissues, depending on the formulation used (granules, gauze, pad).

The safety of using kaolin-based QuikClot intracorporeally compared with standard laparotomy pads was evaluated among 68 patients undergoing damage control laparotomy [43]. No difference in complications rates was detected. Compared with standard sponges, the use of the kaolin-impregnated sponges in 31 infants undergoing the Norwood procedure had a significantly lower intraoperative use of blood products and lower incidence of perioperative bleeding requiring return to operating room for hemostasis (0 versus 41 percent) [44].

Nustat — Nustat consists of hemostatic fibers composed of cellulose and silica. It is approved for use in the United States for external use in rescue and combat situations. The same pad with the addition of a radio-opaque thread, supplied under the name NuStat Trauma Pad, is approved for use inside the surgical field for temporary control of arterial or other brisk bleeding [45].

Biologically active agents — Biologically active agents augment hemostasis. Hemostasis is a dynamic process occurring in four general phases (initiation and formation of the platelet plug, propagation of the clotting through the coagulation cascade, termination of clotting by antithrombotic control mechanisms, and removal of the clot by fibrinolysis). (See "Overview of hemostasis".)

Topical thrombin — Topical thrombin is reconstituted from a lyophilized powder. It can be applied using a sprayer, which is useful for managing diffuse bleeding from oozing peritoneal and pleural surfaces or applied with a syringe to direct its application to a specific area of bleeding. Topical thrombin can also be used in conjunction with a gelatin matrix agent (sponge or granules) that provides the thrombin with an immediate scaffold for clot formation [46-48]. (See 'Gelatin matrix' above.)

Topical thrombin in combination with gelatin foam or granules is useful for promoting hemostasis at vascular graft suture hole sites. Due to its liquid nature, thrombin applied in combination with gelatin granules (eg, FloSeal, Surgiflo) may control bleeding more quickly than thrombin-soaked pieces of gelatin foam. (See 'Effectiveness of hemostatic agents' below.)

Urine does not significantly inhibit the activity of thrombin or thrombin-fibrin combination products at their application site. The urologic literature describes the use of FloSeal gelatin matrix thrombin solution to the partial nephrectomy bed [49]. This may have an advantage over dry matrix agents (and suture material), which can act as a nidus for stone formation [50].

Human thrombin and a recombinant thrombin are available for use, largely replacing bovine thrombin [51]. (See "Fibrin sealants", section on 'Components'.)

Fibrin sealant — Fibrin sealants are typically a two-component system that includes a solution of concentrated fibrinogen and factor XII and a solution of thrombin and calcium. When mixed together just prior to use, a fibrin clot forms. Fibrin sealant can be used to control bleeding at vascular anastomotic sites. They are also used to control bleeding from cut surfaces. Fibrin sealants also have other applications. (See 'Fibrin sealant' below and "Fibrin sealants".)

Tranexamic acid — Tranexamic acid is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules [52]. Systemic tranexamic acid administered at the outset for surgery reduces intraoperative blood loss as well as blood loss from drained spaces such as the knee or mediastinum, but may be contraindicated in patients with intravascular stents or thrombophilia [53]. (See "Initial management of moderate to severe hemorrhage in the adult trauma patient", section on 'Developing treatments for hemorrhage'.)

Topical application of tranexamic acid to the bleeding surface has the potential to inhibit local fibrinolysis at the site of bleeding, reducing bleeding with minimal systemic effects. The effects of topical tranexamic acid have been evaluated primarily during orthopedic surgery [54] but also with head and neck surgery [55], cardiac surgery [56,57], and breast surgery [58]. A systematic review identified 28 trials that compared topical tranexamic acid in surgical patients (cardiac, thoracic, spinal, knee, or head and neck surgery) compared with no tranexamic acid or placebo [59]. Blood loss was significantly reduced in those who received tranexamic acid (pooled ratio 0.71, 95% CI 0.69-0.72), which decreased the need for blood transfusion. The authors noted that there was significant statistical heterogeneity between trials for the blood loss and blood transfusion outcomes. Additional high-quality trials are needed to better identify the effects of topical tranexamic acid on thromboembolism and mortality before topical tranexamic acid can be recommended.

Effectiveness of hemostatic agents — High-quality data establishing the effectiveness of topical hemostatic agents in surgery are lacking. The package insert and US Food and Drug Administration (FDA) medical device application for each hemostatic agent contain data from animal studies and unpublished trials that compare its effectiveness usually with gelatin foam or oxidized regenerated cellulose. Published randomized trials in which topical agents were used for minor intraoperative bleeding sites include the following:

●In three trials involving patients undergoing vascular, spinal, or cardiac surgery, hemostatic sealants (Floseal, Proceed) were found to have significantly higher rates of hemostasis (88 to 99 versus 57 to 93 percent) at 10 minutes after application compared with thrombin-gelatin combination [21,60,61].

●In a trial of 69 patients undergoing obstetric, gynecologic, general, vascular, and cardiothoracic surgery, an autologous fibrin sealant resulted in a significantly higher rate of hemostasis (94 versus 65 percent) at five minutes after application compared with oxidized regenerated cellulose [62].

●In a multicenter trial, 333 patients were randomly assigned to receive the fibrin sealant or a conventional topical hemostatic agent [63]. Fibrin sealant controlled bleeding successfully within five minutes of application in significantly more patients (93 versus 12 percent) compared with conventional topical agents. There were no differences in volume of blood products used or mortality between the two groups.

TISSUE ADHESIVES AND SEALANTS — Tissue adhesives can be used to promote hemostasis but are predominantly used as an alternative to sutures for tissue approximation. Most commonly, cyanoacrylates are used to close minor wounds and skin incisions under low tension in patients who do not have serious medical comorbidities that could impair wound healing. Other agents, such as albumin-based tissue adhesives and polyethylene glycol hydrogels, and surgical applications other than skin closure, have also been investigated.

Fibrin sealant — Fibrin sealants are typically a two-component system that includes a solution of concentrated fibrinogen and factor XII, and a solution of thrombin and calcium. In addition to their hemostatic properties (see 'Fibrin sealant' above), fibrin sealants have properties that make them useful for promoting graft adhesion or to seal leakage. Fibrin sealants are reviewed in more detail separately. (See "Fibrin sealants".)

As an example, in a review of 65 patients who underwent abdominoplasty, fibrin sealant reduced the rate of seroma formation, and when drains were used in combination with fibrin sealant, drain output volume was also reduced [64].

Autologous platelet rich fibrin, which is in growing use for regenerative applications, has also been used as a tissue adhesive and filler in promoting the osteointegration of dental implants and bone augmentation [65].

Cyanoacrylate — Cyanoacrylate tissue adhesives octyl-2-cyanoacrylate (eg, Dermabond) and butyl-2-cyanoacrylate (eg, Histoacryl) are liquid monomers that change to strong polymers with exposure to moisture. The properties of tissue adhesives are discussed elsewhere. (See "Minor wound repair with tissue adhesives (cyanoacrylates)", section on 'Properties of tissue adhesives'.)

Cyanoacrylates are used primarily for skin incision closure during surgery. However, cyanoacrylates have also been used to repair the cornea [66-68]; fixate skin grafts [69]; repair vessels [70,71]; fixate mesh during hernia surgery [72]; during circumcision [73-78]; to seal dural leaks [79], air leaks (ie, bronchopleural fistula), and lymphatic leaks; and endoscopically to seal bleeding esophageal varices or peptic ulcer [9-11]. The use of cyanoacrylates for closure of minor wounds and methods of application are discussed in detail separately. (See "Minor wound repair with tissue adhesives (cyanoacrylates)".)

As a substitute for typical sutured skin closure (eg, subcuticular sutures), tissue adhesives have been used for a variety of open and laparoscopic procedures, including inguinal and femoral hernia repair, testicular surgery, lymph node biopsy, thyroid surgery, hand surgery, excision of skin lesions, blepharoplasty, vein excision, and intraoral surgery [80-96]. The most common elective use of cyanoacrylate tissue adhesive in the operating room is as a final, waterproof seal over subcutaneous absorbable sutures in lieu of a taped-on dressing. Allergic reaction to topical cyanoacrylate is rare, but if it occurs, it is difficult to remove. The treatment in such instance is oral steroids [97].

Compared with traditional, sutured techniques, two separate meta-analyses found that the risk of infection, cosmetic outcomes, surgeon and patient satisfaction, and cost were equivocal between sutured closure and adhesive closure [86,98]. However, suture repair was associated with a lower risk of wound dehiscence. Notably absent from studies evaluating tissue adhesives are procedures involving incisions in areas of high tension (eg, elbow, knee, shoulder). In addition, patients whose medical comorbidities increase the risk for impaired wound healing have also been excluded from such studies.

The larger of these meta-analyses included 26 trials evaluating the use of tissue adhesives for closure of surgical incisions [86]. An earlier updated Cochrane review that included 14 trials (n = 14) had similar conclusions [98]. The updated review identified an additional six studies.

●Among 29 trials that evaluated wound infection rates, no significant differences were found.

●Among 20 trials, wound dehiscence occurred in significantly more incisions closed with tissue adhesives compared with standard wound closure (5 percent [38/762] versus 1.2 percent [9/779]). Adhesives may take more time to apply, and if higher tension is needed upon an incision, sutures may minimize dehiscence

●Among 16 trials comparing the speed of closure using tissue adhesives versus skin sutures, 14 found tissue adhesives to be faster than skin sutures, one found sutures to be faster than adhesives, and one found no difference. Comparing tissue adhesives with staples, three of four studies found staples to be faster; the remaining study found no difference. Compared with adhesive tape, one study found no significant difference.

Albumin based — Albumin-based tissue adhesives combine albumin and an organic compound immediately prior to use. The mixture forms a matrix with adhesive properties. Commercially available compounds consists of a combination of bovine albumin and glutaraldehyde (Bioglue, ArterX) or polyaldehyde (Preveleak) [49,99-106]. Another example is the combination of human albumin and polyethylene glycol (FocalSeal-L, Progel), which has been used to treat pulmonary air leak [107,108]. A trial that compared autologous fibrin tissue adhesive to a commercial preparation and controls that did not receive tissue adhesive application during spinal cord surgery found no difference between autologous and commercial preparations, but, compared with the control group, the volume of cerebrospinal fluid drainage was significantly reduced (586 versus 1026 mL) [109].

Polyethylene glycol hydrogel — A completely synthetic tissue adhesive (CoSeal) combines two forms of polyethylene glycol (PEG) to form a hydrogel. This compound has been used to treat bleeding vascular graft suture holes and has also been used during vitrectomy surgery [110,111]. In a multicenter trial that randomly assigned 148 patients undergoing polytetrafluoroethylene (PTFE) vascular graft placement to PEG hydrogel or thrombin/gelatin sponge, the median time to achieve vascular control was significantly less for those treated with PEG hydrogel (16.5 versus 189 seconds) [110]. However, no differences were seen at the primary endpoint of 10 minutes (86 versus 84 percent). A drawback of PEG hydrogel is its tendency to swell up to four times its initial volume over a 24-hour period, with some continued swelling thereafter, thus limiting its application in confined spaces.

Urethane-based — A synthetic polyurethane tissue adhesive (TissuGlu) has been approved for internal use in the United States based upon studies demonstrating reduced fluid accumulation beneath abdominoplasty flaps without the need for external drains [112-115].

ADVERSE EFFECTS AND COMPLICATIONS — Adverse effects of topical hemostatic agents and tissue adhesives and sealants are related to the composition and characteristics of the preparation, location of placement, and absorption time. Excessive amounts of a slowly degrading product can serve as a nidus for infection, and agents placed into a confined place can cause compression of surrounding structures, particularly if the product has a tendency to expand. As examples, gelatin foam matrix in combination with thrombin has complicated eye and spine surgery, causing blindness and paralysis, respectively [116].

●Air/gas embolism – Air or gas embolism, which has caused death, has been reported with the use of injectable agents such as spray thrombin and fibrin sealant [117-120]. This risk increases when the products are sprayed too close to the tissue or when the maximum pressure recommended in the fibrin sealant kit is exceeded.

●Surgical infection – There are many clinical reports of wound infections associated with the use of hemostatic agents. Adverse factors such as emergency procedure, transfusion, and prolonged operative time are associated with an increased risk of surgical wound infection and frequently coexist with the need for hemostatic agents, and thus, any analysis of the risk of infection due to hemostatic agent is confounded. The risk of infection may be minimized by removing excess topical hemostatic agents from the wound after hemostasis is achieved, when possible.

●Impaired wound healing – Excess application of topical hemostatic agents can impede wound healing. Granuloma formation has been reported with the use of microfibrillar collagen, gelatin foam, and cyanoacrylate [13,121-123]. In addition, the metabolites of cyanoacrylates (ie, cyanoacetate and formaldehyde) can cause an inflammatory response in the surrounding tissues.

●Hypotension – The development of profound hypotension in some individuals after direct parenchymal injection of bovine-derived fibrin sealant is believed to be related to highly concentrated bovine thrombin [124]. The hypotension, which lasts approximately 30 seconds, responds to epinephrine; in addition, this complication can be avoided by reducing the use of bovine thrombin and by compressing the injection sites.

●Anaphylaxis – Allergic reactions (including anaphylaxis) are associated primarily with bovine-derived products (eg, bovine thrombin) [125]. These products should not be used in patients with a history of prior anaphylactic reactions to plasma products or IgA deficiency [46]. A history of prior anaphylactic reactions to plasma products or of IgA deficiency contraindicates the use of fibrin sealants prepared from plasma or cryoprecipitate. (See "Fibrin sealants", section on 'Contraindications'.)

A single case report of a systemic allergic reaction during a laparoscopic cholecystectomy was associated with the use of microfibrillar collagen [126].

●Bloodborne disease – A complication common to all blood components is the potential transmission of an infectious disease, even from screened and tested blood [127]. In addition to the patient, health care workers in the operating room may theoretically be exposed to an infectious disease risk when sealants are applied in an aerosolized form. The use of recombinant human thrombin should reduce the risk.

Nevertheless, although viral transmission is theoretically possible, no cases have been documented with the use of fibrin sealant over the past 20 years, particularly with respect to transmission of hepatitis or HIV. This may be more attributed to extensive viral protection methods, including viral screening (serology and nucleic acid testing [NAT]), complemented by viral reduction methods, including filtration, heat treatment, solvent-detergent cleansing, precipitation, pH treatment, and chromatography. Autologous preparations of fibrin sealant virtually eliminate any infectious disease risk [128-130].

●Vascular thrombosis – No increased rate of vascular or graft thrombosis has been reported with the topical use of hemostatic agents. Although there were concerns in the past that polyester grafts (eg, Dacron) could allow thrombin to leak into the lumen and lead to thrombosis and embolism, this is not an issue with currently available grafts. Topical hemostatic agents should not be injected into a blood vessel or within an opened vessel.

Embolization of gelatin matrix into the bloodstream from spraying it onto the cut surface of bone has been reported [131].

Blood salvage (eg, CellSaver) should not be used when blood has been in contact with gelatin or collagen, because fibers can pass through the filters and cause intravascular coagulation.

●Immune-mediated coagulopathy – A bleeding diathesis can occur in patients who develop factor V deficiency because they make an antibovine factor V antibody (bovine factor V is a contaminant of bovine thrombin preparations) that cross-reacts with endogenous factor V. As discussed above, the use of human thrombin should prevent this complication. (See "Fibrin sealants", section on 'Thrombin'.)

As an example of this issue, in one prospective study of 151 patients undergoing cardiac surgery, 95 and 51 percent of those with prior exposure to bovine thrombin demonstrated a seropositive response to bovine and human coagulant proteins, respectively [132]. The adjusted odds ratio for development of an adverse postoperative outcome was 5.4 when multiple antibodies to bovine coagulant proteins were present preoperatively. Such antibodies may persist for years following the initial exposure to bovine thrombin [133].

CHOICE OF AGENT — The choice of topical hemostatic agents to use depends upon amount and location of bleeding, availability of a given agent, cost considerations, and surgeon preference [134].

Biologically active agents (eg, topical thrombin, fibrin seal) are more useful for brisk bleeding compared with dry matrix agents (eg, gelatin matrix) and are more effective in the setting of coagulopathy or in defibrinated fluid such as pooled serum or cerebrospinal fluid.

Although more expensive, fibrin sealants have significantly higher rates of hemostatic control compared with thrombin-gelatin combinations. Fibrin sealant and bovine albumin-glutaraldehyde tissue adhesive (eg, Bioglue) are appropriate choices when moderate bleeding does not respond to other measures. (See 'Effectiveness of hemostatic agents' above.)

Surgical scenarios — Options for using topical hemostatic agents for various surgical scenarios are given below, including a cost for each agent. Cost key: ¢ = less than 50 United States dollars (USD), $ = 50 to 100 USD, $$ = 101 to 300 USD, $$$ = 301 to 500 USD, $$$$ = 501 to 750 USD.

Large artery bleeding/repair (aorta, femoral, carotid):

●Bioglue ($$$$) is approved in the United States for large vessel repair in cardiovascular surgery.

●NuStat Trauma Pad applied to the bleeding artery will stop bleeding temporarily to allow visibility for control and repair of the vessel and organ.

●Other topical hemostats are not generally approved for arterial bleeding, except microporous polysaccharide spheres (Arista; $), which have been evaluated in a femoral artery porcine model (to a systolic blood pressure of 155 mmHg) [135].

Pulsatile needle hole bleeding in vessel adventitia or in vascular graft material:

●Apply microporous polysaccharide spheres (Arista; $).

●Apply thrombin-soaked gelatin foam (Gelfoam, Surgifoam; $) or oxidized regenerated cellulose (eg, Surgicel; $).

●Apply gelatin matrix-thrombin combination (eg, FloSeal, Surgiflo; $$).

●Spray fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).

Pulsatile external exsanguinating hemorrhage, preoperative setting (arterial rupture, arterial injury):

●Apply compression with external agents (eg, kaolin based [$], chitosan based [$$]).

●Pack with dry fibrin sealant dressing ($$$$+).

Spleen, liver, kidney parenchymal surface post-trauma or partial resection:

●Wrap with oxidized regenerated cellulose (eg, Surgicel; $) or microfibrillar collagen (Avitene Ultrawrap; $$$) with or without suture fixation.

●Apply microporous polysaccharide spheres (eg, Arista) and hold sponge pressure for several minutes ($).

●Spray with thrombin ($).

●Apply gelatin matrix-thrombin combination (eg, FloSeal, Surgiflo; $$).

●Spray fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).

●Apply fibrin glue-oxidized regenerated cellulose "sandwich." This technique has been described for sutureless hemostasis of laparoscopic wedge excisions of the kidney [136].

Venous or capillary oozing from area of dissection or deserosalization:

●Apply oxidized regenerated cellulose (eg, Surgicel Nu-Knit, Surgicel Fibrillar) with sponges and hand pressure ($ to $$).

●Apply microporous polysaccharide spheres (eg, Arista) and hold sponge pressure for several minutes ($ to $$).

●Spray with thrombin ($ to $$).

●Spray with fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).

Cavity or potential space, nerve or other tissue not amenable to cautery, need to avoid compression of nerve:

●Apply microporous polysaccharide spheres (eg, Arista) and hold sponge pressure for several minutes. Irrigate away remaining powder ($).

●Avitene Flour, EndoAvitene (OK to leave in place; $$).

●Spray with fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).

Cost considerations — Topical hemostatic agents are usually prepackaged for one-time use in quantities that are generally sufficient to manage bleeding from a single site. Although these preparations should not be used unnecessarily, they are cost effective if they save operative time, reduce transfusions, and prevent a return to the operating room. The cost of these agents falls in the range between an electrosurgery pen and the handset of various tissue-sealing energy sources (eg, ultrasonic desiccator).

Less expensive agents are frequently used in a routine or preventive setting to minimize blood loss. The more expensive agents (fibrin sealants and microfibrillar collagen) are often more effective in the setting of coagulopathy or anticoagulation and are frequently the preferred choice when bleeding is not easily controlled. (See 'Effectiveness of hemostatic agents' above.)

Although it is easy to compare the direct cost of the various topical hemostatic agents, it is difficult to assess the associated costs of surgery related to hemostatic agents, such as operating room time and blood transfusion products. Using length of stay (LOS) as a rough estimate of cost, a study of 36,950 patients correlated length of stay after cardiothoracic surgery with the choice of hemostatic agent and found significantly less likelihood of exceeding expected LOS for fibrin sealant (FloSeal) compared with other hemostatic agents (Surgicel plus thrombin, Gelfoam plus thrombin) [137].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acquired bleeding disorders" and "Society guideline links: von Willebrand disease".)

SUMMARY AND RECOMMENDATIONS

●Indications – A major goal during any surgery is minimization of blood loss, which reduces the need for blood transfusion. Bleeding during surgery is controlled using standard surgical techniques such as electrocautery, vessel ligation, and suturing. Topical hemostatic agents and tissue adhesives are useful adjuncts to manage bleeding from surgical surfaces and are particularly useful for diffuse nonanatomic bleeding, bleeding associated with sensitive structures, and bleeding in patients with hemostatic abnormalities. (See 'Introduction' above.)

●Hemostatic applications – Hemostatic agents work primarily by exerting physical effects or by enhancing existing hemostatic mechanisms (table 1). Physical agents include dry matrix agents, bone waxes, and external agents. Biologically active agents that enhance normal hemostatic mechanisms include thrombin-based products, fibrin sealant, tranexamic acid, and others. (See 'Hemostatic agents' above.)

●Tissue adhesive applications – Tissue adhesives can be used to promote hemostasis and are also used as an alternative to traditional closure of surgical incisions. Agents include cyanoacrylates, albumin-based adhesives, polyethylene glycol hydrogels, and urethane-based agents. Agents with adhesive qualities are most commonly used to close surgical skin incisions or minor wounds, but other applications in surgery have been investigated. For skin closure using cyanoacrylates, the risk of infection, cosmetic outcomes, and cost are similar between sutured closure and adhesive closure. However, sutured closure is associated with a lower risk of wound dehiscence and is quicker to accomplish. (See 'Tissue adhesives and sealants' above.)

●Adverse effects – Adverse effects and complications from topical hemostatic agents and tissue adhesives are generally uncommon. Most problems can be avoided by limiting the amount of agent remaining within the wound once hemostasis has been achieved. Thrombin-based agents, which are blood products, have the potential for transmission of bloodborne disease, and anaphylaxis and immune-mediated coagulopathy are rare complications associated with bovine-derived agents. Other complications include embolism, infection, impaired wound healing, and thrombosis. (See 'Adverse effects and complications' above.)

●Agent selection – The choice of which topical agent to use depends upon the character, amount, and location of bleeding; the availability of a given agent; surgeon preference; and cost considerations. Dry matrix agents are less useful when bleeding is brisk. Fibrin sealant and bovine albumin-glutaraldehyde tissue adhesive (eg, Bioglue) are appropriate choices when moderate bleeding does not respond to other measures. (See 'Choice of agent' above and 'Effectiveness of hemostatic agents' above.)