Ann Thorac Surg 2009;88:1377-1383. doi:10.1016/j.athoracsur.2009.02.092
© 2009 The Society of Thoracic Surgeons
Review
A Review of Topical Hemostatic Agents for Use in Cardiac Surgery
James Barnard, MD, MRCS,
Russell Millner, MD, FRCS(CTh)*
Department of Cardiothoracic Surgery, Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, United Kingdom
* Address correspondence to Mr Millner, Department of Cardiothoracic Surgery, Blackpool Victoria Hospital, Whinney Heys Rd, Blackpool, FY3 8NR, United Kingdom (Email: russellmillner{at}btinternet.com).
| Mr Millner discloses that he has a financial relationship with MedTrade Products Limited.
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Abstract
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Postoperative hemorrhage, redo sternotomy for bleeding, and transfusion of blood products are all associated with poorer outcomes in cardiac surgery. Topical hemostatic agents are important adjuncts to reduce blood loss after cardiac surgery and can have a role in reducing both "surgical" and "nonsurgical bleeding." There are many topical hemostatic agents to choose from, and with several new products in this field being approved for use in the last few years, the aim of this review is to appraise these agents and to look at the evidence for their efficacy.
Hemostatic agents are a useful tool in reducing perioperative and postoperative bleeding. Patients coming forward for urgent cardiac surgery may have been exposed to aspirin, clopidogrel, or glycoprotein IIb–IIIa inhibitors, in addition to heparin or warfarin resulting in a higher degree of postoperative bleeding [1]. Prolonged time on cardiopulmonary bypass, cooling, and heparinization all contribute to the derangement of blood clotting mechanisms and predispose the patient to postoperative bleeding. Excessive bleeding may necessitate transfusion of blood products with potential associated adverse effects, including anaphylactic transfusion reactions, transfusion-related lung injury, and transmission of infectious agents. Postoperative hemorrhage, transfusion of blood products, and re-exploration for bleeding [2] are all associated with poorer outcome in cardiac surgery. Surgical causes of postoperative bleeding are found in 66% of cases on re-exploration with the remainder being attributed to coagulopathy [3]. Surgical bleeding is considered to be bleeding at the site of a surgical suture line or anastomosis, whereas nonsurgical bleeding is hemorrhaging of small vessels from a tissue surface and is generally accepted as being as a result of a coagulopathy. A variety of topical hemostatic agents are used with varying efficacy and varying degrees of evidence in favor of their benefits (Table 1). Several new agents have been approved for use in the last few years, including chitosan-based agents, which have shown great promise in controlling major hemorrhaging in the pre-hospital setting and in animal models of major hemorrhaging [4]. The aim of this review is to discuss agents that are presently used and agents that are also presently used in other fields and may have an important role to play in cardiac surgery.
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Methods
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A systematic English language literature search was conducted using MEDLINE and PubMed between January 1974 and August 2008. Keywords used for the search included bleeding, hemostatic agent, sealant, and cardiac surgery. Additional reports were identified by references cited in the publications found using the search terms and also in published review articles. Emphasis was placed on randomized controlled studies where possible.
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Compression Hemostatic Agents
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Compression hemostatic agents absorb blood and provide a scaffold for clot formation in addition to exerting compression on a bleeding site.
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Oxidized Regenerated Cellulose
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Surgicel, Oxycel
Surgicel (Johnson & Johnson Medical Inc, Arlington, TX) is a local hemostatic bioabsorbable gauze consisting of oxidized regenerated cellulose. It is a poly anion, the functional unit of which is polyanhydroglucuronic acid. Surgicel provides a scaffold on which platelets can commence the adhesion and aggregation process leading to coagulation, but it is not reported to alter the physiological clotting mechanism. There is evidence of absorption within the first day, and complete absorption can be observed between 4 to 8 weeks, the rate being dependent on the volume of surgicel, local vascularity, and the nature of the tissue bed. Surgicel is also reported to be bacteriostatic [5] with reported antimicrobial activity, even against antibiotic-resistant micro-organisms including MRSA [6].
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Collagen
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Colgel, Helitene, Avitene
Microfibrillar collagen was initially described in 1969. It is a water-insoluble acid salt of bovine collagen, which when used topically adheres to the bleeding site and provides some hemostatic effect and initiates platelet activation and aggregation, as well as reinforcing the fibrin clot that is formed. For high transfusion risk cardiac surgery patients, including repeat cardiac operations (such as aorta coronary bypass operations or valvular operations), ascending aortic aneurysm repair necessitating deep hypothermic circulatory arrest and ascending aortic grafting without deep hypothermic circulatory arrest Surgicel has been compared with microfibrillar collagen hemostat (Colgel [Laboratorie Interphar, Aubervilliers, France]) in terms of the ability to reduce postoperative bleeding and was found to be superior in terms of reducing postoperative drainage (Table 1) [7]. Microfibrillar collagen is not as good at reducing infection risk as Surgicel [5] and is reported to cause end-organ damage if shed blood containing it is returned to the circulation by either pump suction or cell salvage devices, as it may readily pass through the filters of these devices [8].
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Composite Collagen and Thrombin Sealant
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CoStasis
CoStasis (Cohesion Technologies, Palo Alto, CA) is a composite of bovine microfibrillar collagen and bovine thrombin in a calcium chloride buffer mixed intraoperatively with an equal volume of autologous plasma obtained at the time of operation. The patient's plasma provides fibrinogen that is cleaved by the thrombin to form a collagen-fibrin gel matrix. The composite is delivered as a spray onto the bleeding site. CoStasis (Cohesion Technologies) has been compared with the use of gauze and collagen sponges and has been shown to achieve hemostasis within 3 minutes in cardiac surgery patients undergoing cardiopulmonary bypass for coronary artery bypass grafting in 76% of cases compared with 46% achieved in the control group [9]. The study does not give exact details regarding the site or timing of application, and the use of CoStasis did not have any impact on reducing transfusion of blood products.
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Thrombin Sealants
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Thrombin, Thrombogen, Thrombistat
It is estimated that thrombin has been used as an adjunctive hemostat in more than half a million surgical procedures per year in the United States [10]. Thrombin is a serum protease that transforms fibrinogen into fibrin, and activates factor XIII and promotes stabilization of the clot formed by fibrin and other proteins. The majority of thrombin used is derived from bovine plasma, although in January 2008, recombinant human thrombin (Recothrom [ZymoGenetics, Seattle, WA]) gained United States Food and Drug Administration (FDA) approval and has potential advantages in comparison with the bovine or human types, including reduction in the formation of patient thrombin antibodies and exclusion of the risk of transmission of infection while maintaining comparable efficacy [11].
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Cyanoacrylate Sealants
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Omnex
Omnex (Ethicon Surgical Sealant; Ethicon Inc, Somerville, NJ) is a synthetic tissue adhesive consisting of a blend of two monomers (ie, 2-octyl cyanoacrylate and butyl lactoyl cyanoacrylate). The liquid preparation is contained inside a crushable capsule that delivers the preparation through a porous disc, which contains an initiator agent to activate the delivered sealant. The sealant polymerizes to form a flexible sealing film, which is adherent to both synthetic material and human tissue in a process that is independent of the patient's clotting processes. The seal degrades with time, breaking down into smaller absorbable fragments.
A prospective, randomized controlled trial has assessed the efficacy of cyano-acrylate sealants in establishing hemostasis of expanded polytetrafluoroethylene to arterial vascular anastomoses in arteriovenous grafts and femoral bypass grafts in 151 patients [12]. The mean time from clamp release to hemostasis was 119.3 seconds with cyanoacrylate surgical sealant versus 403.8 seconds, with the control (oxidized cellulose) (p < 0.001). Immediate hemostasis was achieved in 54.5% of patients receiving cyanoacrylate surgical sealant and in 10% of those receiving the control. A subsequent study in patients undergoing arteriovenous access or vascular reconstruction below the diaphragm with the use of cyanacrylate sealant found that immediate hemostasis was achieved in 71.3% (112 of 157) of sites and in 93.6%, 96.8%, and 100% within 1, 5, and 10 minutes, respectively [13].
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Fibrin Sealants
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Tisseel, Beriplast, Hemaseel, Crosseal/Quixil, Vivostat
Fibrin sealant was developed in 1972 by Matras and colleagues [14] by successfully using a fibrinogen cryoprecipitate in peripheral nerve anastomoses on animal models. Fibrin sealants are made of two components contained in separate vials: (1) a freeze dried concentrate of clotting proteins, mainly fibrinogen, factor XIII, and fibronectin (ie, the sealant) and (2) freeze dried thrombin (ie, the catalyst). Fibrinogen is a precursor of fibrin, which represents the basic element of the clot. The transformation of fibrinogen into stable fibrin occurs by means of thrombin and factor XIII, which in turn are activated by thrombin. Fibrin sealants emulate the final stages of the clotting cascade, but as they are autonomous of the body's clotting mechanism, they are also effective in patients with coagulopathies or those who are receiving heparin or anticoagulants [15, 16].
Historically there have been concerns about the use of fibrin sealants with so-called homemade preparations used until the 1990s, predating the United States FDA approval, containing cryoprecipitate not subjected to viral inactivation and containing variable levels of impurities [17]. Tisseel (Baxter Healthcare, Fremont, CA) and Beriplast (CSL Behring, King of Prussia, PA) contain bovine aprotinin, whereas Crosseal (Ethicon Inc), marketed in the United Kingdom as Quixil, contains tranexamic acid. These agents are added as antifibrinolytic agents to slow fibrinolysis of the clot, which is produced at the site of application. After a recent report of increased mortality with the use of aprotinin in cardiac surgery patients [18], Bayer Pharmaceuticals have notified the FDA of their intent to remove their systemically administered aprotinin agent Trasylol from hospital pharmacies. Tisseel (Baxter Healthcare) and Beriplast (CSL Behring) are not affected by this withdrawal, although there are reports of the adverse effects of bovine aprotinin in sealants relating to the highly immunogenic nature of bovine aprotinin in humans. Over 125 anaphylactic reactions having being reported in the literature, with an estimated anaphylaxis incidence of between 0.5 and 5 per 100,000 topical applications [15]. The Vivostat system (Vivostat A/S, Birkerod, Denmark) is a medical device to produce an autologous fibrin sealant CE marked for use in Europe in 2000. The FDA approval for use of Vivostat (Vivostat A/S) in the United States has been applied for but was not yet granted at the time this article was written. The device can generate 4.5 mL of sealant from 120 mL of the patient's blood in 23 minutes [19]. The sealant is applied using a spray system. There is no randomized controlled trial using this system in cardiac surgery in which it is compared with a comparable sealing agent, although its tensile strength has been compared with other fibrin sealants and has been found to be comparable [20].
Kjaergard and Fairbrother [21] have reported 24 trials of the use of fibrin glues in cardiothoracic surgery, with 20 trials reporting a positive benefit in terms of reducing bleeding, 4 studies reporting no difference from controls, and no studies reporting a negative influence on bleeding. More recently a randomized controlled trial in pediatric cardiac surgery cases with a proven coagulopathy has shown a significant reduction in the use of blood products and operating room time to achieve hemostatsis when fibrin sealant has been used [22].
A note of caution should also be raised in the use of fibrin sealants in coronary artery bypass grafting as Lamm and colleagues [23] have reported an increased risk of myocardial injury or even death in cornary artery bypass grafting patients when Tissucol fibrin sealant was used intraoperatively. They reported that in several cases they had an acute occlusion of bypass grafts after Tissucol was applied in proximity to the anastomoses with immediate embolectomy showing fresh fibrin clot in the lumen of the grafts in each case. This study resulted in the product description being changed to specifically emphasize that special care was necessary when using Tissucol in aortocoronary bypass operations.
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Polyethylene Glycol Polymers
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CoSeal, DuraSeal
Polyethylene glycol polymers are synthetic hydrogels intended specifically as tissue sealants (ie, derivatives of polyethylene glycol); they can propagate rapid cross linking with inherent proteins, such as collagen, to form a cohesive matrix that adheres strongly to the applied tissue. The sealing capability of the hydrogel is almost immediate and does not require any human blood products or bovine components to inhibit bleeding. In a randomized controlled trial, the effectiveness of CoSeal (Cohesion Technologies, Palo Alto, CA) was compared with Gelfoam (Upjohn, Kalamazoo, MI) and thrombin for managing anastomotic bleeding after implantation of Dacron grafts (DuPont, Wilmington, DE) during aortic reconstruction for nonruptured aneurysms. A significantly greater proportion of bleeding suture line sites treated with CoSeal (Cohesion Technologies) achieved immediate sealing after re-establishment of bloodflow [24]. Another randomized controlled trial of CoSeal versus Gelfoam (Upjohn) and thrombin during surgical placement of prosthetic vascular grafts showed that overall 10-minute sealing success was equivalent. However, subjects treated with CoSeal achieved immediate anastomotic sealing at more than twice the rate of subjects treated with Gelfoam and thrombin [25]. Duroseal is rarely used in cardiac surgery, although an experimental trial was performed to examine whether it had any benefits in reducing adhesion formation post-cardiac surgery and no benefit was proven [26].
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Bovine Albumin and Gluteraldehyde
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BioGlue
BioGlue (CryoLife Inc, Atlanta, GA) is a bovine serum albumin and glutaraldehyde tissue adhesive. Two separate solutions are dispensed by a controlled delivery system, composed of a double-chambered syringe. Once dispensed, the adhesive solutions are mixed within the applicator tip where cross-linking begins. The glutaraldehyde molecules covalently bond the bovine serum albumin molecules to each other and, upon application, to the tissue proteins at the repair site, creating a flexible mechanical seal independent of the body's clotting mechanism. BioGlue (CryoLife Inc) begins to polymerize within 20 to 30 seconds and reaches its bonding strength within 2 minutes. BioGlue also adheres to synthetic graft materials through mechanical interlocks within the interstices of the graft matrix.
A randomized controlled trial has compared the use of BioGlue with a standard control repair of anastomotic bleeding in patients undergoing cardiac and vascular repair. In this study, 49 patients underwent cardiac procedures, 105 aortic procedures, and 48 peripheral vascular procedures. Anastomotic bleeding was significantly reduced in the BioGlue group (18.8% of anastomoses) compared with the control group (42.9% of anastomoses; p < 0.001). Pledget use was reduced in the BioGlue group (26.2%) compared with the control group (35.9%; p = 0.047) [27].
Adverse effects have been reported with the use of BioGlue including nerve tissue injury [28], leaking of the BioGlue through needle holes [29], and impaired aortic growth causing anastomotic strictures [30]. BioGlue is not recommended in pediatric surgery due to its inability to allow growth of the tissue it is used on. Caution must be exercised in the application of BioGlue as it may spread away from the site of application and has even spread onto valve prostheses causing intraoperative dysfunction [31, 32].
There have been concerns raised regarding the potentially harmful effects of BioGlue to local tissues. Anecdotal reports detail the persistence of BioGlue years after application surrounded by unusually soft and friable native tissues suggesting that BioGlue may impair normal healing [30, 33, 34].
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Gelatin and Thrombin
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FloSeal
FloSeal Hemostatic Matrix (Baxter Healthcare Corp, Freemont, CA) is a combination of a bovine-derived gelatin-based matrix and a human-derived thrombin component. On contact with blood, the gelatin particles swell and tamponade the bleeding, while the high-thrombin levels quicken clot formation. The thrombin used in FloSeal (Baxter Healthcare Corp) is manufactured from pooled human plasma subjected to a two-step vapor-heat treatment that has been demonstrated to significantly reduce viral load; however, as stated by the manufacturer, no procedure has been shown to be completely effective in removing viral infectivity from derivatives of human plasma. FloSeal is completely absorbed within 6 to 8 weeks of application.
In a prospective, randomized study, conducted by Oz and colleagues [35], 93 patients undergoing cardiac operations were randomized into the FloSeal or control group after standard surgical means to control bleeding had failed. FloSeal stopped bleeding in 94% of the patients (first bleeding site only) within 10 minutes, compared with 60% in the control group who received Gelfoam thrombin (p = 0.001). At 3 minutes, successful hemostasis was achieved in 72% of the FloSeal group compared with 23% in the control group (p = 0.0001). Success in the FloSeal group was achieved in 26 of 27 patients treated after protamine reversal of heparin and in 17 of 19 patients treated before heparin reversal. In the control group, hemostasis success was achieved in 21 of 28 patients treated after protamine reversal of heparin and in 5 of 14 patients treated before heparin reversal. The success of hemostasis in the FloSeal group was statistically, significantly better than the control group before protamine reversal of heparin (p = 0.0023). Success rates between the two groups did not reach statistical significance after protamine reversal of heparin (p = 0.051) [35].
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New Agents: Microporous Polysaccharide Hemospheres
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Arista AH, HemoStase MPH
Arista AH (Medafor Inc, Minneapolis, MN) and HemoStase MPH (Cryolife Inc) are simple, safe, and effective hemostatic powders recently approved by the FDA for most types of surgery including cardiac, orthopedic, spinal, and general surgical applications. Microporous polysaccharide hemospheres are plant-based and are delivered as a flowable powder engineered to rapidly dehydrate blood, enhancing clotting on contact. This osmotic action causes the particle to swell and concentrates serum proteins, platelets, and other formed elements on its surface. The particles and their coating of compacted cells create scaffolding for the formation of a tenacious fibrin clot within minutes of application. The particles are fully absorbed and enzymatically cleared from the wound site within 24 to 48 hours. There are no trials reporting the use of these agents for hemostasis in cardiac surgery published in the literature.
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Chitin and Chitosan-Based Hemostatic Agents
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HemCon, Closure, Chitoseal, or Celox
Chitin polymer (β-(1
4)-N-acetyl-D-glucosamine) is a naturally occurring polysaccharide synthesised by a large number of living organisims and exists as a crystalline microfibril forming structural components in the exoskeleton of arthropods and in the cell walls of fungi and yeasts. Chitosan was first reported to be of potential use in cardiovascular surgery in 1983 when it was shown to form a coagulum when in contact with defibrinated blood, heparinized blood, and washed red cells. When knitted DeBakey grafts were treated with Chitosan, they were found to be impermeable to blood [36].
Reports have indicated that Chitin and Chitosan accelerate blood coagulation in vivo, and that in addition they enhance the release of platelet derived growth factor-AB and transforming growth factor-β1, which play important roles in the wound healing process [37]. Coagulation and haemagglutination tests have shown that the hemostatic mechanism of Chitiosan seems to be independent of the classical coagulation cascade and seems to be an interaction between the cell membrane of erythrocytes and Chitsoan [38].
Celox (SAM Medical Products, Portland, OR) is a granular hemostatic agent that interacts directly with red blood cells and platelets to form a cross-linked barrier clot, independent of native factors. It is reported by the manufacturer to be nonallergenic, nonexothermic, able to function in a hypothermic environment, and low in cost. HemCon (HemCon Medical Technologies Inc, Portland, OR) is one of the two most common hemostatic dressings used by the United States military in treating casualties in the pre-hospital setting, and it is coated with Chitosan. QuikClot (Z-Medica Corp, Wallingford, CT) contains zeolite powder that absorbs water from the blood, thereby concentrating clotting factors. A randomized controlled trial using a porcine model of acute arterial and venous hemorrhage has compared hemorrhage control, rebleeding, and survival between Celox (SAM Medical Products), HemCon (HemCon Medical Technologies Inc), QuikClot (Z-Medica Corp), and standard gauze dressings. All agents controlled initial vascular bleeding; Celox reduced rebleeding to 0% (p < 0.001); HemCon reduced rebleeding to 33% (p = 0.038); QuikClot reduced rebleeding to 8%. Celox improved survival to 100% compared with 67% for HemCon and 92% for Quik Clot. At our institution we have used Celox as a topical hemostatic agent in cardiac surgery patients and have found it easy to use and highly efficacious [39].
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Comment
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Choice of one topical hemostatic agent in comparison with another is variable from one surgeon to another and may depend on individual experiences and availability rather than a strong evidence basis. Efficacy in the control of bleeding within a 10-minute timeframe has been reported for thrombin (95%) [11], Floseal (96%) [40], and CoStasis (97%) [9]. A direct comparison has been made between Floseal, Gelfoam, Avitene, Surgicel, and fibrin sealants in an animal model of aortic arterial bleeding in the presence of heparin. In this model fibrin sealant was proven to be the most efficacious hemostatic agent [16]. However, detailed comparisons between hemostatic agents in animal studies are difficult, as clotting mechanisms outside of primate studies differ substantially.
The published studies in this field are heavily dominated by trials that have been funded by the manufactures of the hemostatic agents that are being tested (Table 1). In the absence of well-controlled clinical trials, a sound evidence basis for the use of one agent in comparison with another will not emerge. The Society of Thoracic Surgeons Blood Conservation Guideline Task Force have recommended that topical sealants used to assist in the repair of complex, high-risk cardiac and aortic procedures are not unreasonable to limit bleeding in certain key situations (eg, left ventricular free-wall rupture and aortic dissection), but they are associated with complications that may limit their usefulness in less high-risk situations.
Several of the hemostatic agents discussed in this review contain bovine or human-derived components (Table 2). As with any animal-derived or human plasma-derived component, immunological reactions may occur causing severe hypotension, systemic inflammatory responses, and in rare cases, anaphylaxis. In addition, with bovine or human-derived plasma components, there is a small risk of transmission of viral agents, and this is stated in the manufacturer's product information. With any bovine sourced components, there is a risk of transmission of bovine spongiform encephalopathy, but there is no evidence that such an event has occurred. There has been a reported case of viral transmission with the use of an adhesive agent prepared from human plasma [41], but this pre-dates the current stringent collection and testing processes, and the current techniques used to reduce viral load.
Importantly, surgeons should note that hemostatic agents carry warning labels detailing contraindications to their use. One of the important contraindications is the use of these agents in patients with antibodies against bovine antibodies. As the study by Weaver and colleagues [42] details, 27% of patients exposed to agents containing bovine thrombin develop these antibodies and hence should not be exposed to bovine thrombin-containing agents if future surgery is necessary. The Society of Thoracic Surgeons Blood Conservation Guideline Task Force have recommended that topical hemostatic agents that use bovine thrombin are not helpful for blood conservation during cardiopulmonary bypass and may be potentially harmful [43].
From a practical perspective, the cirmcumstances surrounding the desire to use a hemostatic agent are crucial to the choice of agent. Hemostatic agents that accelerate clot formation have the disadvantage that they are only effective against surgical bleeding when hemorrhage is minimal, and must therefore be applied before removal of the cross clamp or while at very low flow on cardiopulmonary bypass. In essence this relegates these agents to either a prophylactic role in which the surgeon must always anticipate excess hemorrhage in advance, or their use necessitates reducing flow rates while on cardiopulmonary bypass or while re-applying the cross clamp, or with both of the latter two situations. The alternative option favored by some surgeons in this scenario may be to use the bovine serum albumin and gluteraldehyde tissue adhesive with its ability to rapidly form a mechanical seal that is independent of native clotting factors and which forms even in the presence of some bleeding. The disadvantages of using the albumin and gluteraldehyde combination include the reported risks of embolization, local tissue destruction, and the bovine source of the albumin with the related risks or anaphylaxis. A further strategy is to deploy one of the compression hemostatic agents, such as oxidized regenetrated cellulose gauze. This offers the advantages of reducing active bleeding, providing compression, and providing a scaffold for clot formation. The disadvantages of using the compression hemostatic agents is that they may not offer a definitive solution to prevent further bleeding, they can not enhance the process of clot formation in coagulopathic patients, and they can be responsible for postoperative infections.
There is a need for caution when choosing hemostatic agents while still on cardiopulmonary bypass or while using cell salvage systems. Microfibrillar collagen agents can pass through filtration systems causing end-organ damage, sponge fabric materials, such as Surgicel, Gelfoam Sponge, and Hemopad can activate the clotting cascade causing the cell salvage system to clot off and liquid agents, such as thrombin and thrombogen may create a fibrin clot by direct action on fibrinogen, again clotting off the cell salvage system.
The ideal topical hemostatic agent would be one that was deployable even against brisk hemorrhage, which was independent of native clotting mechanisms and would not pass through salvage filtration systems, and which was not sourced from a bovine or human origin. With the development of recombinant thrombin and an increasing number of agents that do not contain any animal or human-sourced components, it may be that there is a shift away from older hemostatic agents. Preliminary results from animal models show great promise for Chitosan-containing agents that are inexpensive, bio-absorbable, do not contain any human or bovine-derived components, and have no risk of viral agent transmission. Clinical trials are required to delineate the potential benefits of these newer agents and establish their efficacy in comparison with currently used hemostatic adjuncts.
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Footnotes
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* Studies marked with an asterisk are those which have declared commercial sponsorship. 
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Abstract
Introduction
