Haemostatic sealants in nephron-sparing surgery: what surgeons need to know

Authors


Dalpiaz Orietta, Department of Urology, Medical University Innsbruck, Anichstrasse 35 6020- Innsbruck, Austria.
e-mail: orietta.dalpiaz@uki.at

Abstract

Surgical haemostatic agents have been increasingly applied for the control of bleeding, and have excellent potential in laparoscopy. Several factors are important when evaluating the use of sealants. We present a brief overview of the history, composition and mechanism of action of sealants, together with a report on experimental studies and clinical experience with haemostatic sealants. We searched for reports on haemostatic agents and their use in renal parenchymal haemostasis; 15 animal models studies and 11 papers on clinical experience were included. The development of haemostatic agents and instruments is allowing the wider diffusion of challenging procedures. Several experimental animal studies have shown the efficacy and safety of sealants for haemostasis during nephron-sparing surgery. Clinical studies confirm the effectiveness of synthetic or fibrin glue, in particular during laparoscopic surgery. Sealants are effective and safe topical agents to control bleeding during nephron-sparing surgery. They should not be viewed as an alternative, but as complementary agents to be used to improve surgical outcomes. Further prospective studies are necessary to validate their role in relation to other haemostatic support techniques.

Abbreviations
NSS

nephron-sparing surgery

FDA

Food and Drug Administration

GRFG

gelatine-resorcinol formaldehyde-glutaraldehyde.

INTRODUCTION

Tissue sealants or glues are surgical haemostatic agents and have been increasingly applied in urological surgery in the last two decades, with excellent potential in laparoscopy [1]. Minimally invasive nephron-sparing surgery (NSS) has become a standard approach and largely replaced open surgery in the management of renal masses [2]. However, the laparoscopic and the more recent robotic approach remain technically challenging procedures because of difficulties in haemostasis and managing collecting-system injuries [3]. Therefore, several new techniques, instruments and agents have been proposed to control bleeding during renal surgery [4]; the efficacy and safety of sealants has been widely reported [5].

However, it is important to consider several factors when evaluating the use of sealants. In this review we provide a brief overview of the history, composition and mechanism of action and current use of haemostatic products, and address specially urologists interested in NSS. Furthermore, the different available products, their characteristics and history are discussed, hopefully enabling surgeons to use them critically during surgery.

METHODS

We searched for available reports on sealants and their use in NSS; studies were identified by searches of Medline and the Cochrane Database, using an unrestricted search strategy with specific terms (synthetic glue, fibrin glue or seal, fibrin sealant, biological glue, nephron-sparing surgery, partial nephrectomy, laparoscopy) and exploded Medical Subject Headings. Manufacturers’ websites were searched and bibliographic references of key papers were also considered. Animal studies and systematic reviews were included. Studies on the use of sealants in open or laparoscopic NSS were selected that contained reports on their composition or the name of the manufacturer. Those using glue and other haemostatic techniques were also included. This review is based on the 15 animal model studies and 11 clinical papers that were identified by the search.

FIBRIN GLUE

HISTORY

During World War II several methods were described for fractionating pooled plasma into various protein components, including fibrinogen and thrombin, facilitating haemostasis [6]. Commercial products became available in Europe in the late 1970s and after the USA Food and Drug Administration (FDA) revoked the license for their clinical application because of the risk of transmitted blood-borne infections. Various home-made preparations were used. With the advent of multiple viral inactivation procedures, fibrin glue has again been licensed in the USA and Europe. Tisseel (Baxter Healthcare, Deerfield, IL, USA) was the first commercially available fibrin sealant approved by FDA in 1998.

MECHANISM OF ACTION AND COMPOSITION

In the last decades there had been a proliferation of commercial virus-inactivated or virus-removed fibrin sealants. They can be produced from pooled blood sources or from a single blood donor, and which can be allogeneic or autologous. The use of pooled blood products is the basis for most of the commercially available fibrin sealants. Irrespective of the method of preparation, fibrin glues mimic the last step of the clotting cascade (Fig. 1). Blood coagulation is based on the activation of fibrinogen to fibrin by thrombin. Through the action of activated thrombin, the fibrinogen is cleaved of peptides, thereby converting it into a soluble monomer. These fibrinogen monomers are cross-linked to an insoluble fibrin matrix by the action of activated factor XIII. The cascade process is independent of the internal clotting mechanism, thus resulting in haemostasis even in the presence of systemic coagulation defects [7].

Figure 1.

The coagulation cascade and mechanism of action and site of preparations.

THROMBIN COMPONENT

Thrombin is a highly specific protease and needs ionic calcium to activate factor XIII, which facilitates the cross-linking of soluble fibrin polymers, creating insoluble fibrin polymers and greatly increasing the clot stability (Fig. 1). Bovine thrombin (e.g. Thrombinar, Armour Pharmaceutical Co., Collegeville, PA, USA) or heat-treated products prepared from pooled plasma are currently available (Table 1). Most preparations also contain aprotinin to delay fibrinolysis and to increase the lifespan of the clot [8].

Table 1.  Commercial surgical sealant products and mechanism of action
MaterialCommercial nameManufacturerMechanism of actionWhat it needs to work
Fibrin glue or variantsCrosseal (trexanemic acid)Johnson & JohnsonMixes fibrinogen, thrombin and factor XIII dispensed from a  double-barrel syringe to generate clot.
Also includes aprotinin to prevent fibrinolysis
Fibrin glue must be warmed before use (20–40 min)
Tisseel (bovine aprotinin)Baxter (Immuno)
HemaseelHealthcare Corp.
CoStasis (bovine collagen  and thrombin + patient  derived fibrinogen)Haemacure Corp.Include collagen, but not aprotininApply to a dry stationary  tissue surface
DynastatCohesion Corp.
Vivostat (autologous)Vivolution
ThrombinThrombinarArmour Pharm.Interacts with fibrinogen in the patient’s blood to form a fibrin clotCirculating fibrinogen and a means of delivery for use on active bleeding
Thrombin JMIGentrac, Inc.  
CollagenAvitene (sponge)CR Bard, Inc.Contact activation and promotion of platelet aggregation to initiate the clotting cascadeFunctional clotting cascade and all clotting factors
FloSealBaxter HealthcareGelatine granules restrict the flow of blood, provide a physical matrix around which a clot can form, and deliver and maintain thrombin to the tissue surfaceCirculating fibrinogen
TachoComb/TachoSilNycomedCollagen fleece coated with fibrin 
Absorbable gelatineSurgifoamJohnson & JohnsonInitiation of clotting cascade through contact activationFunctional clotting cascade and all clotting factors
SurgiFloJohnson & Johnson  
GelfoamPfizer  
CelluloseSurgicel (oxidized regenerated cellulos)Johnson & JohnsonCellulose fibres initiate clotting cascade through contact activationFunctional clotting cascade and all clotting factors
AldehydeBioGlue (albumin and glutaraldehyde)Cryolife, Inc.The glue cross-link with proteins in tissue forming a strong adhesive 
CyanoacrylateGlubranGlubran UK Medical Ltd  
DermabondEthicon, USA  

FIBRINOGEN COMPONENT

Fibrinogen can be obtained from pooled or single donor blood, platelet-rich plasma or autologous blood, which would potentially eliminate the risk of transmission of infection. It might contain other plasma proteins that contribute to the clotting process, such as fibronectin or factor XIII (a fibrin-stabilizing factor; Fig. 1). Cryoprecipitation is the standard for fibrinogen preparation, but chemical precipitation with ammonium sulphate, polyethylene glycol or ethanol might be more feasible for concentrating the fibrinogen from small amounts of autologous blood [9]. The advantage of chemical concentration would be that the processing time is minutes rather than hours for the cryoprecipitation techniques, but it has the disadvantage of chemical additives. However, the frozen plasma method is more expensive and does not meet the standards for the closed system required for safe handling and management of blood-component products. A comparative study showed that the concentration of fibrinogen prepared from pooled human blood is higher than those from autologous or single donor sources [10]. Before the approval of fibrin sealants by the FDA, surgeons used so-called ‘home-made’ sealants, combining bovine thrombin and human fibrinogen from pooled cryoprecipitate or autologous fibrinogen [11]. Various methods have been described for preparing fibrin sealant from autologous or single-donor blood [12]. Autologous blood can also be collected directly in the operating room, as described by Kjaergard et al.[13].

The composition of the products affects the properties of the resulting fibrin clot and might influence their use in different surgical procedures. Sealants with a high concentration of fibrinogen tend to produce stronger clots, whereas those containing higher concentrations of thrombin form clots rapidly. The latter is essential when rapid haemostasis is required to stop blood loss. Fibrin degradation products, originating from proteolytic cleavage of the fibrin clot, stimulate the migration of monocytes which then convert to macrophages to remove degraded fibrin by phagocytosis [14]. By contrast with synthetic materials, the plasma-derived fibrin sealant has the advantage of being biocompatible, biodegradable and absorbable, with no significant inflammation, foreign-body reactions, tissue necrosis, or extensive fibrosis, which can be associated with synthetic agents [15].

SYNTHETIC GLUE

Synthetic sealants such as cyanoacrylate, or products based on collagen, oxidized cellulose or gelatine, contain monomers that polymerize after contact with tissue, forming an adhesive layer with high resistance. This film conforms to the tissue surface and is not impaired by blood or urine. The polymerization time depends on the type of tissue with which the product comes into contact, the amount and the nature of fluids present, and the amount of product applied. The glue starts to set after a few seconds and completes the reaction after ≈2 min, but has little or no haemostatic effect in heparinized patients, or if platelets have been inactivated by drugs. The synthetic film is impermeable and is eliminated by hydrolysis. Once set, the film can be easily perforated by a suture needle. Early experimental and clinical studies reported highly promising results of fibrin and gelatine-resorcinol formaldehyde-glutaraldehyde (GRFG) glues, comparing their haemostatic effectiveness, tensile strength, tissue reaction, adhesion formation, and glue resorption time [16]. Both were equally effective in controlling bleeding and were better than the suture controls. Histologically, both fibrin sealant and GRFG glues produced a relatively acellular layer of loose connective tissue. However, large fragments of the GRFG were evident after 6 weeks and were associated with inflammatory changes. A potential advantage of synthetic sealant is that it is not antigenic and carries no risk of viral infections. Table 1 lists the various commercial products currently available and their mechanism of action.

METHODS OF APPLICATION

Synthetic glues are ready for use and require no preparation; they are stored in mono-dose vials and should be aspirated just before use, then applied drop by drop. Fibrin glue can be sprayed or applied using a dual-syringe system. Commercial kits usually contain separate vials containing fibrinogen and thrombin and sometimes other additives in solution. The two components can then be applied sequentially or simultaneously to the surgical field by a dual-syringe system. The device enables simultaneous application of equal amounts of the fibrinogen and thrombin solutions, which travel through a common joining piece mixing uniformly before being expelled. Various applicator designs have been proposed to improve this system, using a combination of positive gas and vacuum pressure as well as manual force to actuate or augment the delivery of fibrin glue. Laparoscopic applicators are also available [17]. The mixed solution can either be applied to a small area using a cannula or over a larger area with a spray tip. In the spray technique, fibrinogen and thrombin concentrates are sprayed simultaneously using specific devices comprising a multi-lumen catheter usually connected to a gas-propellant system for aerosolization. It is especially helpful for ensuring homogeneous glue application as a fibrin film on diffuse slow-bleeding and large surfaces. To evaluate the function of commercial applicators, one should consider several variables that reflect the advantages or disadvantages of any particular design, as well as cost-effectiveness. For example, the time required for assembling the applicator, transferring the vial components into the applicator, or starting glue delivery is a factor to be considered. Furthermore, the number of needles required to reconstitute or transfer liquid solutions and the total number of parts (e.g. vials, needles) that are needed to be handled should also be considered.

Other variables that affect the rating of an applicator might be requirements for external vacuum or air pressure lines, internal clogging waste, or the need for a refrigerator or freezers. Ease of use, safety and costs of delivery are other factors to consider, and each should affect the choice. Adhesive patches are also available and comprise layers of collagen, fibrinogen, thrombin and aprotinin dried together. These preparations are particularly indicated with soft bleeding organs where suturing and cautery might not be effective.

ADVERSE REACTION OR COMPLICATION

VIRAL TRANSMISSION

Products made from human plasma carry a theoretical risk of viral transmission, such as hepatitis B and C, HIV and other blood-borne viruses. This concern caused delayed approval of a commercial product in the USA. However, no cases of serious viral transmission after the use of fibrin sealant have been reported. In the last decades advances in viral inactivation technology have resulted in a decreased risk of viral transmission, and heat treatment has been shown to be capable of significant viral reduction [18].

Despite this technology, thermoresistant viruses, e.g. hepatitis A and parvovirus B19, could not be eliminated. Most adults have antibodies to parvovirus B19 and some manufacturers recently introduced PCR-based testing to screen for viral antigens. The infection, if it occurs, is usually mild. Sealants made from animal or human proteins can theoretically transmit viral or prion disease vectors; Creutzfeldt-Jakob disease represents a theoretical risk, although no case has been reported so far. Careful donor-selection strategies are crucial and blood bank-produced fibrin can eliminate these risks only when autologous blood is used.

ALLERGIC REACTIONS

Bovine thrombin can be immunogenic and can cause allergic reactions. Patients treated with bovine thrombin preparations often develop antibodies to plasma proteins, which are clotting factors or glycoproteins involved in coagulation. Antibodies to these bovine proteins could be responsible for causing significant anticoagulation by cross-reacting with human homologues; immunologically induced coagulopathy has been reported [19]. However, the clinical significance of these various antibodies and their role in bleeding and thrombosis is still unclear. The problem has been addressed by adopting human thrombin in most preparations. Anaphylaxis has been also reported as a rare event after the use of fibrin sealants. Aprotinin was shown to be responsible for anaphylaxis in at least one patient. The reported frequency of hypersensitivity to i.v. aprotinin is ≈10%. After application of synthetic preparations, temporary local inflammatory reactions or allergic complications have also been described. Table 2 summarizes the comparison (characteristics, application, safety issues and reproducibility) between synthetic and fibrin products.

Table 2.  Comparison between synthetic and fibrin products
 Synthetic productsFibrin glues
CompositionCyanoacrylate, collagen, oxidized celluloseFibrinogen and/or thrombin
ActionPolymerization after tissue contactMimic of last step of coagulation
CharacteristicsStandardized tensile strength and adhesivenessConcentration of fibrin and  thrombin affects the sealing  properties
Possible inflammatory changes or foreign-body  reactions fibrosisBiocompatible, biodegradable,  absorbable
Ready for useRequire preparation
ApplicationMono doseSyringe system
Safety issuesNo viral transmission riskSingle donor; Screening tests or  viral reduction
Treatment in pooled blood
ReproducibilityStandardizedLess reproducible (?)

ANIMAL STUDIES

Chang et al.[20], in 1992, showed that fibrin glue obtained from single-donor fresh-frozen plasma accelerates the coagulation plug formation and enhances the mechanical strength of the adhesive plug. Gelfoam, used as a vehicle to hold the fibrin glue, was more efficient than gauze or collagen fleece in achieving haemostasis. In the same year, another report [21] compared the efficacy of different haemostatic agents in a rat kidney model. The materials used were oxidized cellulose, microfibrillar collagen powder, collagen and single-donor heterologous fibrin glue, with no statistically significant differences in their activity. Table 3[22–34] lists animal models, emphasising the effectiveness of sealants in achieving immediate and durable haemostasis in renal parenchyma.

Table 3.  Urological applications of sealants on animal models, and clinical experience in NSS
StudyNo. of pigs/ patientsType of surgeryHilar controlType of gluesHaemostasisLeakage
  1. (L)PN, (laparoscopic) partial nephrectomy; LHN, laparoscopic heminephrectomy; ha LPN, hand-assisted; LWR, laparoscopic wedge resection; na, not available.

Animal
[22]18PNyesFibrin adhesive bandageyesno
[23] 3LPNyesPEG-lactideyesno
[24] 11LHNyesSealant dry powder (HFSP)yesn.a.
[25] 8PNnoFibrin and Gelfoamyesno
[26]16PNnoFibrin glueyesno
[27] 9LPNnoCyanoacrylateyesno
[28]15PNyesBioGlue and Crossealyesno
[29]16LPNyesCoSealyesyes
[30]50PNyesFibrin glueyesno
[31] 8ha LPNnoFloSealyesno
[32]15PNyesTisseel and FloSealyesno
[33]n.a.PNyes7 different agents (synthetic and fibrin)yesno
[34] 5grade 5 lacerationcoolingFloSealyesno
Clinical
[35] 7PNyesSuture and mixture of autologous fibrin and bovine-derived thrombinyesna
[36] 5LPN4 yes; 1 noHarmonic bipolar and glue (resorcinol and formaldehyde)yes1
[37]2515 PN;yesFlosealyesna
10 LPN    
[38] 6LPNyesGelatin matrix thrombin sealantyesna
[39]15ha LPNcompressionArgon-beam and Tisseelyesno
[40]15LWR15%Ultrasonic shears, argon-beam coagulation Tisseel and Surgicel  (sandwich)yesna
[41]63LPNyesFlosealyesna
[42]75ha LPN27%Argon and FG (FloSeal, Tisseel and Gelfoam)yesna
[43]31PNyesBioGlueyesna
[44]10LPNyesAutologous fibrin glue (Vivostat system)yesna
[45]44LPNyesFlosealyesna

In a recent prospective randomized study on porcine kidney, a complex hypothermic grade 5 renal injury was created and treated by applying FloSeal gelatine matrix (Baxter Healthcare). The sealant produced a rapidly effective haemostasis with no bleeding or nephrotoxicity, suggesting a possible role even in the treatment of devastating renal injuries [34].

CLINICAL APPLICATIONS

Numerous centres have reported that sealants can be used to decrease bleeding during NSS. Most of the published reports discuss the use of sealants for laparoscopic surgery (Table 3) [35–44]. In a study comparing fibrin sealant with a sutured bolster, fibrin sealant provided adequate haemostasis after laparoscopic partial nephrectomy when the collecting system or renal sinus was not entered [41]. A technique for achieving effective haemostasis using the Vivostat system (Alleroed, Denmark) for preparing autologous glue was recently reported, with encouraging results [43]. Although hilar clamping provides a bloodless surgical field, renal ischaemia carries a significant risk of renal ischaemic injury. Triaca et al.[45] recently described the use of thrombin sealant with no renal artery occlusion in open partial nephrectomy, and concluded that partial nephrectomy with no temporary arterial occlusion is technically feasible and safe. The use of glue could avoid the need for renal artery occlusion and can prevent subsequent renal failure. Finley et al.[40] achieved excellent haemostasis with a fibrin glue-oxidized cellulose sandwich during laparoscopic wedge resection. After coagulation of the tumour bed, layers of Tisseel and Surgicel were applied, with no complications. Although fibrin sealant has been applied with good results, other haemostatic aids, such as argon beam and bipolar coagulation or sutures, are often used in combination, making an evaluation of the relative merit of sealant difficult and confusing. Johnston et al.[41] recently proposed practical recommendations on the use of glues, determining which technique is best, based on tumour depth of penetration and proximity to renal sinus.

FUNCTIONAL SIGNIFICANCE

Only one paper reported the effect of using glue on renal function [42]. The authors compared changes in renal function after NSS using tissue adhesive only (24 patients) vs NSS using a standard suturing technique (32 patients), as measured by quantitative single-photon emission CT and 99mTc-DMSA uptake by the kidney. In the tissue sealant group (19 with albumin glutaraldehyde tissue adhesive, BioGlue; and five with CoSeal) after surgery there was a mean individual renal functional loss of 11%, compared with the suture group in whom the mean loss was 20% (P = 0.02). From this study the use of tissue sealant to close the parenchymal defect during NSS had a statistically significant advantage in reducing functional renal loss, as measured by the absolute uptake of DMSA. Further clinical studies are required to establish the role of tissue sealants in NSS.

PRACTICAL PROBLEMS

The first practical problem is the type of bleeding that must be controlled. After applying the products it takes 60–90 s for the clot to form. Arterial bleeding could wash the glue away before a clot can be produced, and the use of glue is therefore most effective on relatively dry surfaces with diffuse slow ooze, or in sealing.

Regarding particularly the synthetic products, after the components have been applied, the surgeon should hold the sealed parts in the desired position for at least 3–5 min to ensure that the setting glue adheres firmly to the surrounding tissue. This manoeuvre could be difficult under laparoscopy.

Sealants should not be injected directly into large blood vessels or through suture line defects, to avoid the possibility of thromboembolic complications, or unintentional and unwanted ‘trickle’ into another part of the surgical field, with adverse consequences.

When solutions expand, they could constrain or compress the anastomotic sites and this is particularly important with smaller structures like grafts. This concept is particularly important for agents that have toxic components or cause a vigorous inflammatory response. Finally, a sealant that is also an adhesion barrier might paradoxically predispose to anastomotic leak or pseudo-aneurysm, by preventing the tissue growth that might normally intervene and protect against these late sequelae.

Another issue that must be considered is the time required to prepare fibrin glues and devices, as reported above. These products in particular require dissolving the fibrinogen component. This means that the product must be prepared in advance and is less suitable for use in such situations where bleeding occurs unexpectedly. Finally, the application of products must be completed within 4–8 h after reconstitution.

ECONOMIC CONSIDERATIONS

Despite several studies showing the safety and efficacy of sealants in achieving haemostasis, there are few published reports addressing the cost-effectiveness aspects of their use. Jefferies et al.[46] reported that 5–8.6% of total costs of 60 university hospitals were attributed to all aspects of blood transfusion costs. A Cochrane review on seven clinical trials reported that fibrin sealant treatment reduces the rate of exposure to allogeneic red cell transfusion by a relative 54%. Furthermore, it reduced blood loss on average by around 134 patients in 442, resulting in an effective reduction of both postoperative blood loss and peri-operative exposure to allogeneic red blood cell transfusion [47] and thus costs can be reduced greatly. The potential economic benefits of improving surgical haemostasis and minimizing transfusions are:

  • • reduced costs of blood and blood product transfusion;
  • • reduced costs associated with complications of transfusions;
  • • decreased operating time;
  • • reduced stay in critical care unit;
  • • reduced hospital stay.

Pharmaco-economic studies are required to better define the place of haemostatic agents in improving the safety and simplicity of surgical procedures and decreasing the costs.

CONCLUSION

An increasing number of studies confirm the effectiveness of haemostatic agents in achieving renal parenchymal haemostasis, in particular during mini-invasive approaches. Different products and the current use of other support haemostatic techniques make the comparison of studies difficult. However, with adequate knowledge of the available haemostatic techniques and products, surgeons can choose those methods and agents that are most suitable under the given patient conditions, and thus improve the surgical outcome of challenging procedures.

CONFLICT OF INTEREST

None declared.

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