Topical hemostatic agents in surgery : review and prospects

Hemostasis plays a critical and fundamental role in all surgical procedures. Its management has several key points that start with good operative technique and adequate anesthetic support. Certain situations, such as severe bleeding resulting from penetrating trauma, do not depend exclusively on the control of the surgical team and require the support of new solutions that decrease or control bleeding. Since ancient times, a hallmark of medicine has been to act in the control of hemorrhage, and more recently, in the facilitation of hemostasis by the application of topical agents by either manual compression or modern agents. In the last decade, the number of different topical hemostatic agents has grown dramatically. For the modern surgeon to choose the right agent at the right time, it is essential that he/she understands the mechanisms of action, the effectiveness and the possible adverse effects related to each agent. Thus, the great variety of topical hemostatics, coupled with the absence of a review article in the national literature on this topic, stimulated us to elaborate this manuscript. Here we report a detailed review of the topical hemostatic agents most commonly used in surgical specialties.


INTRODUCTION
H emostasis plays a critical and fundamental role in all surgical procedures.Its management has several key points that start with good operative technique and adequate anesthetic support.Certain situations, such as severe bleeding resulting from penetrating trauma, do not depend exclusively on the control of the surgical team and require the support of new solutions that decrease or control bleeding.
The use of topical hemostatics is an old concept, used in different ways by ancient civilizations.The Egyptian people made use of a mixture of wax, grease, and barley in an effort to stop bleeding.In ancient Greece, priests and healers of the time applied hemostatic herbs to war wounds 1

. Recently, advances in
Rev Col Bras Cir 45 (45):e1900 cellulose (ROC) -appeared on the market with the launch of Surgicel®, the only one hitherto not derived from human or animal elements 2 .ROC is therefore a topical hemostatic of vegetal origin, manufactured by the regeneration of pure cellulose in interwoven (cotton) fabric that is subsequently oxidized.Its functional unit is anhydroglucuronic acid.The regenerated oxidized cellulose is easy to apply and manipulate in surgery because of its loose interwoven fabric, resembling a cotton swab (Surgicel Fibrillar®, Gelitacel®) or a small piece of mesh (Surgicel Nu-Knit®), thus acting as a support matrix for the initiation and formation of the clot.The regenerated oxidized cellulose is not sticky, adheres to surgical material, can be molded in different shapes and sizes, does not chip in the presence of liquids and supports compression without losing its property.This material should not be infused into aqueous media prior to use, since it has improved hemostatic activity when applied dry.and which can also be attributed to gelatinousbased hemostats, is the postoperative appearance of an image with a hyperdense halo and hypodense center at tomography, which may be confused with an abscess.Non-common images that generated diagnostic doubt were recently reported in the literature in both adults and pediatric patients.More than that, surgical complications were reported with the use of ROC in cases of severe bleeding 4,5 .The dissolution of ROC can range from two weeks to a few years, depending on the amount of the product used 3 .
Gelatins (Surgifoam®, Gelfoam®, Gelfilm®, Gelita-spon®, Geli putty®, FloSeal®) Gelatin is a hemostatic agent made from hydrolyzed and purified animal collagen (swine, sheep or equine dermis or tendon).It was introduced in the market in 1945 and few advances in its form and composition have been made since 6 .Although its mechanism of action is not fully known, it is believed to act more physically than chemically in the coagulation cascade 7 .Thus, as in the ROC case, gelatins are useful as a physical matrix for clot initiation.
The gelatin matrix can be used in different forms: sponges, powder and sterile physiological solution to form a foamy appearance when mixed or saturated in purified thrombin.The foamed solution is associated with a decrease in infection at the site of application and has been shown to be useful in reducing bleeding of bone origin, as in sternotomies and neurosurgeries.
An important property of the different forms of gelatin is its ability to absorb more than 40 times its weight in blood and fluids and its ability to expand its volume by 200% in vivo.This means that gelatin forms increase their volume more than the topical hemostatics based on collagen and regenerated oxidized cellulose.Although this property provides good hemostatic mechanical action, it can also be seen in some ways as a negative feature in some specialties, especially when used in confined spaces or near nerve structures, generating complications of compressive origin.The general and trauma surgeon can benefit from this property in penetrating traumas.Transfixant wounds from solid organs, in particular, may be handled with this material alone or in conjunction with ROC.
Studies reporting complications related to the use of gelatins, such as formation of abscesses or granulomas, are rare.Some attribute these complications to doubtful postoperative radiological images, later identified as topical gelatine hemostatics 8,9 .
The gelatin matrix is absorbed within four to six weeks and is referred to as non-antigenic, although it is derived from products of animal origin.
Unlike regenerated oxidized cellulose, the pH of the gelatin matrix is neutral and therefore can be used and human thrombin solution that are mixed at the time of use 10,11 .In contact with blood, the gelatin particles swell and induce a buffering effect.This feature allows it to be more effective in controlling moderate bleeding compared with other agents.
FloSeal® has been be superior to Gelfoam-thrombin in cardiac surgeries and has reduced bleeding when used in open nephrectomies and laparoscopy 12 .
Although not important in certain surgical TMC provides a generous surface area that, when in contact with blood, allows adhesion and platelet activation, promoting thrombus formation within two to five minutes 14

BIOLOGICAL AGENTS
Fibrin sealants (Evicel®, Tisseal®, Crosseal®, Quixil®) The Fibrin sealant was first mentioned in the literature in 1909, in Europe.Studies resumed in the 1940s after the availability of purified thrombin and its use became common in different surgical specialties, including during the First World War.In the USA, it was approved for use in humans only in the 1980s (Tisseal®), after proving to be safe and effective 16 .
The classic fibrin sealant consists of clustered human lyophilized fibrinogen and bovine or human thrombin, sometimes also containing concentrated coagulation factor XIII and aprotinin 17 .
Factor XIII is a proenzyme activated by thrombin in the presence of calcium ions (fibrin stabilizing factor).Once activated, factor XIII forms cross-links between fibrin chains, stabilizing the clot formation.
Being the oldest type of glue on the market, several products are available, with varying concentrations of its ingredients.This modifies the coagulation properties.Blood clots' resistance to traction is a function of several factors and the concentration of fibrinogen is of great importance.Thrombin has a major impact on the speed and integrity of coagulation and, indirectly, on clot stability 18 .
Aprotinin is a protease inhibitor (bovine lung tissue) that inhibits trypsinin, plasmin and kallikreins, delaying plasmin-mediated clot lysis.Fibrin glues are applied through a double syringe technique.
Ideal application requires a dry operating field.
Fibrin glues are particularly effective when applied prior to bleeding.In this situation, fibrinogen may polymerize before blood pressure increases the flow of the local microcirculation.When used after the onset of bleeding, one should apply local pressure over the wound to allow polymerization 19 .
The  [25][26][27] , which resembles a spongy plaque and demonstrated its utility not only as a hemostatic, but also in intestinal anastomoses and in tracheobronchial fistulas due to its high adhesive capacity 25,28 .To date, no adverse effects have been related to the use of TachoSil®, although there have been reports in the literature of the presence of antibodies after its application, but without clinical expression 27 .
It is formed from prothrombin, as a result of the activation of intrinsic and extrinsic coagulation pathways, and forms the base of the fibrin clot, promoting the conversion of fibrinogen to fibrin.
Thrombin has been purified from several sources and used as an adjunct to topical hemostasis for more than 60 years.Until recently, the only commercially available thrombin was derived from bovine plasma (Thrombin-JMI).Although it been an effective tool to stop bleeding, bovine thrombin has been shown to induce an important immune response 29 .
Several studies have documented a number of clinical events that accompany human exposure to bovine thrombin, and include the development of antibodies against thrombin, prothrombin, factor V, and cardiolipin 29 .Patients on hemodialysis with high levels of antibodies against topical bovine thrombin had an increased incidence of vascular access thrombosis, severe coagulopathy and bleeding after exposure to bovine thrombin 30 .
Because of these concerns, researchers have developed thrombin derived from human plasma and recombinant human thrombin.In 2007, Browman et al. 31 demonstrated, in a comparative study between recombinant human thrombin and bovine thrombin, that human recombinant thrombin demonstrated the same efficacy in surgical hemostasis, a similar safety profile, and a significantly lower immune response than bovine thrombin.

Glutaraldehyde and bovine albumin adhesive (BioGlue®)
The glutaraldehyde and bovine albumin adhesive (GBAA) consists of a solution of 10% glutaraldehyde and 45% bovine albumin solution purified by precipitation, heat and chromatography radiation 32 .It was approved for use in the USA in 1999, being commercially presented in a syringe with two separate compartments and the same dispensing nozzle, when its components are then mixed at the time of application.Within 20 seconds the adhesive has 65% binding power and obtains its full binding strength in two minutes, regardless of the temperature or the application medium (air or water) 33 .In a study in which BioGlue® was used as a hemostatic agent in 79 cardiac surgeries, there was success in 78 cases.
Although some research in cardiac surgery suggests the use of BioGlue® in pericardial sutures and vascular prostheses, its indication still seems controversial in this and other surgery segments 33,34 .
Recently, an Austrian group conducted an interesting experimental study comparing the use of GBAA and fibrin sealant in inguinal hernia surgeries.According to the authors, GBAA demonstrated good binding potency, but low biocompatibility (cytotoxicity).They also found persistent inflammatory activity, thus not favoring the use of this material in this specific indication 35 .An experimental study with young pigs on aorto-aortic anastomotic reinforcements also reported persistent inflammatory reaction resulting in stenosis, compromising its indication in children and youngsters 36 .On the other hand, another experimental analysis suggested the use of GBAA as a reinforcer of gastrointestinal anastomoses performed by staplers; however, the authors affirm that more studies are necessary to determine whether or not GBAA is able to prevent or assist in cases of anastomotic fistulas 37  Complications related to embolization have also been described and its indication seems to be controversial 42

(
acid) to form acid hematin.One of the theoretical advantages of low pH is the potential antimicrobial action and caustic action, potentiating hemostasis and the formation of an artificial clot 1 .The low local pH, however, has the disadvantage of inactivating the action of biologically active coagulants, such as thrombin, thus preventing the use of ROC in conjunction with other biological hemostatic agents.In addition, the acidic nature of ROC can increase the local inflammatory process and delay the normal healing process 3 .Another important point, which may induce the surgical team to submit their patient to unnecessary intervention, interventions, FloSeal's liquid property facilitates application in certain procedures and techniques, especially in minimally invasive surgery.It has been demonstrated that the use of FloSeal® in surgery is safe and effective 10,12 .Developed and marketed in the 1970s, topical microfibrillar collagen (TMC) hemostats are produced by purifying bovine, equine or goat collagen fibers (dried protein), processed into microcrystals and then handled in commercial forms.The Avitene® brand was first launched in powder form, and is still commonly used.All types of collagen-based hemostats gained widespread early use when they appeared to be more effective than topical gelatin-based hemostatics.Collagen-based products activate the intrinsic pathway of the coagulation cascade, while the gelatine-based hemostats induce hemostasis through physical properties.In some randomized clinical trials, microfibrillar collagen hemostats were superior to regenerated oxidized cellulose, demonstrating a statistically significant reduction in blood loss 13 .Advances in the field of collagen-based hemostats have been the launch of new commercial formats.The first collagen-based topical hemostatic (Avitene®) was initially available in powder form, and today the product line has expanded into tissuelike materials, as well as sponge-shaped and small pads or plaques (Instat®).

Table 1 .
Types, trade name and mechanism of action of topical hemostatic agents.
. Complications and doubtful interpretations in imaging methods are also reported in the literature in several surgical areas, including Cardiothoracic Surgery and Neurosurgery 38 .
to use and when becomes often confusing.A better understanding of the various types of topical hemostatics and the practical experience gained will allow the surgeon to form an appropriate critical sense to indicate the right agent at the appropriate time.The ideal agent is that easy to use, effective, usable in any or most surgical conditions, non-antigenic, fully absorbable and affordable.We believe that the advancement of bioscience and the realization of new experimental and clinical research will define the hemostatic agent of better cost benefit.A hemostasia tem papel crítico e importância fundamental em todos os procedimentos cirúrgicos.Seu manejo possui diversos pontos chaves, que se iniciam por boa técnica operatória e adequado suporte anestésico.Determinadas situações, como hemorragias graves resultantes de trauma penetrante, por exemplo, não dependem exclusivamente do controle da equipe cirúrgica e necessitam do apoio de novas soluções que diminuam ou controlem a hemorragia.Desde os tempos antigos, um marco da medicina é atuar no controle da hemorragia e, mais recentemente, na facilitação da hemostasia pela aplicação de agentes tópicos, seja por compressão manual ou agentes modernos.Na última década, o número de diferentes agentes hemostáticos tópicos cresceu drasticamente.Para que o cirurgião moderno escolha o agente correto no momento correto, é essencial que conheça o mecanismo de ação, entenda a eficácia e os possíveis efeitos adversos relacionados a cada agente.Assim, a grande variedade de hemostáticos tópicos, somada à ausência de um artigo de revisão na literatura nacional sobre este tópico, nos estimulou a elaborar este manuscrito.Aqui relatamos uma revisão detalhada sobre os agentes hemostáticos tópicos mais comumente utilizados nas especialidades cirúrgicas.