Reviews
Fibrin glue: the perfect operative sealant? J.W. GIBBLEA N D P.M. NESS
DESPITETHE DEVELOPMENT OF modern surgical techniques and improvements in intraoperative hemostasis, the search for the perfect hemostatic agent continues.’ Technologic advances have included improved suture materials, metallic staples and clips, and a variety of natural and synthetic hemostatic agents including collagen products (i.e., collagen fleece), absorbable gelatin sponges, oxidized cellulose, and synthetic cyanoacrylate-based glues. Fibrin glue (fibrin sealant) has been advocated by many surgeons as the material that best approaches the ideal operative sealant. Abundant reports have appeared, touting its beneficial properties. As a naturally occurring and partially human-derived product, the material appears to have no tissue toxicity, promotes a firm seal in seconds to minutes, is reabsorbed in days to weeks following application, and appears to promote local tissue growth and r e ~ a i r . The ~ . ~ use of this material outside of the United States, particularly in Europe, has flourished. Its use within the United States has lagged more than a decade behind that in Europe, largely because of the lack of ready access to commercially prepared material^.^ The rationale for the exclusion of commercially prepared products from the United States market will be examined in this article. We will also review the development of fibrin glue, its composition and mechanism of action, alternatives to commercial products, and current indications for the use of this material. Historical Perspective
Interest in the use of fibrinogen as a natural surgical adhesive began the early 1 9 0 0 and ~ ~ there was additional experimentation in the 1940s. As detailed by MatrasY2 early studies concentrated on the direct application of fibrin powder or fibrin tampons to bleeding surfaces. Later, more sophisticated attempts used a fibrinogenthrombin clotting system to anchor skin grafts. In general, the adhesive qualities of these preparations were poor. Most authors2.’ have cited a lack of a concentrated source of fibrinogen as the reason for the suboptimal adhesive properties used in these early experiments. The From [he Amcrican Rcd Cross, Blood Scrvices, Chcsapcakc Rcgion, Baltimorc, Maryland, and thc Johns Hopkins School of Mcdicine Baltimorc. Reccived for publication Sepfembcr 6 , 1989; revision received January 29, 1990, and accepted March 12, 1990.
741
concept of a fibrin sealant system became a reality in the early 1970s, when techniques for the isolation and concentration of clotting factors were improved. In 1972, Matras et al.6 described the successful application of a fibrin glue system for peripheral nerve repair. Their method is similar to modern commercial systems of fibrin glue application. Since the time of that study, numerous articles investigating and expanding the potential applications of fibrin glue have appeared in the world literature. Because fibrin glue methods depend on a consistent and concentrated source of human fibrinogen, investigation in the United States was largely halted in 1978 when the Food and Drug Administration revoked the license for the clinical use of pooled commercial fibrinogen concentrates. This ban, which was based on the well-recognized observation of the high risk of hepatitis transmission by f i b r i n ~ g e n ,eliminated ~ the importation into the United States of commercially prepared fibrin glue systems. Such products currently available in Europe include Tisseel (Immuno, Vienna, Austria) and Beriplast (Behringwerke AG, Marburghhn, FRG). Their advantages are ready availability and consistent provision of a source of fibrinogen and other constituents. Standardized manufacturing processes ensure an acceptable product with increased likelihood of uniform performance in the surgical field. Plasma- and cryoprecipitate-based methods for the production of fibrin glue (for individual patients) have been developed in the United States, but the use of fibrin glue remains limited here, because these methods are viewed as time-consuming, cumbersome, and unpredictable. Components and Mechanism of Action
The mechanism of the fibrin glue system mimics the final stage of the coagulation cascade, in which fibrinogen is converted to fibrin in the presence of thrombin, factor XI11 (FXIII), fibronectin, and ionized calcium. The Tisseel fibrin sealant system allows this reaction to be examined in greater depth. The kit consists of a vial of lyophylized concentrated fibrinogen that also contains fibronectin, FXIII, and reduced amounts of plasminogen. The concentrate is reconstituted with a solution containing aprotinin, which is a bovine-derived protease inhibitor with antifibrinolytic activity, the addition of which theoretically enhances the persistence of the fibrin
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GIBBLE AND NESS
clot or seal. (Studies to date do seem to support this concept.) The fibrinogen and aprotinin solutions are combined, mixed thoroughly, and warmed to 37°C. The second component of the kit, bovine thrombin, is reconstituted with a calcium chloride solution. The thrombin is present in the kit in concentrations of 4 and 500 NIH units, and the concentration can be selected for slower (4 NIH units) or faster (500 NIH units) clotting, as needed. Application is usually carried out with a double-barreled syringe apparatus (Dupolject, Immuno), which allows for simultaneous application through a blunt-tipped needle of equal amounts of the fibrinogen and thrombin solutions. Alternatively, the materials can be applied by spray application with forced sterile gas, by mixing equal proportions of the solutions on application. Although not as effective as these equal mixing techniques, sandwich applications of the materials (a layer of fibrinogen solution followed by a layer of thrombin solution) have been successful in oral surgical procedures and for the application of collagen fleece to wound surfaces.2.8 The reaction proceeds by thrombin cleavage of fibrinopeptides A and B from the fibrinogen molecule, which results in the formation of fibrin monomers. Thrombin also activates FXIII, which in turn allows for stable fibrin cross-linkage (in the presence of ionized calcium) and the formation of a firm, nonfriable clot. Fibronectin is also a participant in fibrin cross-linkage, and its inclusion in the fibrin glue system appears to promote cellular migration and fibroblastic growth into areas of fibrin seal application.2 A modification of the basic fibrin sealant system includes the incorporation of the kit materials into layered collagen fleece (FTCH, Hormon-Chemie, Munich, FRG). The fibrinogen-to-fibrin conversion is promoted by application to wet tissue surfaces, which brings the incorporated thrombin in contact with f i b r i n ~ g e n . ~ Alternatives to Commercial Fibrin Glue
The risk of virus transmission by commercial fibrin glue products is still debated. Theoretically, viruses remaining in these topical preparations could be adsorbed and retained by the patient, which could result in the transmission of hepatitis B, non-A,non-B hepatitis, HIV-1, and possibly other blood-borne viruses, such as HIV-2. However, much literature reports the absence of documented cases of virus transmission after the use of fibrin glue p r o d u ~ t s . * ~ Ca' ~ ~i n' ~et- ~al.I3 ~ summarized several European studies that failed to show evidence of disease transmission in over 1 million patients who underwent operations in which commercial fibrin glue was used. The general absence of such virus transmission appears to be due to careful donor selection, extensive virologic and alanine aminotransferase (ALT) testing,
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and heat treatment of these products.'J4 Despite these intensive efforts to eliminate disease risk, many investigators seem to retain some doubt as to the safety of these products. Restricted access to European commercial fibrin sealant systems has resulted in the investigation of alternative fibrinogen sources in the United States. Many of these studies have relied on autologous or single-donor cryoprecipitate as a source of f i b r i n ~ g e n . ~ . ' ~Autolo-~' gous-source fibrinogen eliminates the risks of virus transmis~ion.'~Although single-donor and autologous cryoprecipitate methods produce limited amounts of fibrinogen concentrate, the yields are usually sufficient for most types of operative procedure. However, the use of autologous blood units or samples necessitates preoperative planning, and those products are not generally available for emergency therapy. Single-donor cryoprecipitate methods have been more widely applied, as the cryoprecipitate is readily available, and the associated risk of viral disease transmission is equivalent to that with transfusion of single-donor blood products. In the simplest terms, cryoprecipitate methods combine the direct application of thawed cyroprecipitate to the bleeding surface and the application of bovine topical thrombin (usual concentration, 1000 units/mL). 15-18 The clotting reaction is enhanced when thrombin is reconstituted with calcium ~ h l o r i d e . ' ' . ~As ~ a rule, antifibrinolytic agents such as aprotinin are not included in these cyroprecipitate-thrombin glue mixtures. The significance of this omission will be reviewed shortly. Modifications of the basic cryoprecipitate method described above (see Table 1) include the addition of a centrifugation step to concentrate further the precipitated fibrin~gen.~.'"~'In these studies, centrifugation speeds and times ranged from 1000 x g for 15 minutes to 6500 x g for 5 minute^.^.^^ Wan et a1.22 combined a repeat freeze-thaw cycle with centrifugation (4200 rpm) and complete plasma drainage to enhance fibrinogen yields. Other investigators used chemical additives to increase fibrinogen yields. Such methods included ammonium sulfate precipitation or the addition of polyethylene glycol (PEG).5.'0.23-25Durham et al.'O and Seidentop et suggested the safety of ammonium sulfate precipitation methods for in vivo use. Weisman et al.' and Silberstein et al.2' demonstrated the efficacy and safety of PEG methods for topical applications in the middle ear. Comparative studies have shown that the commercially prepared Tisseel product generally contains the highest concentration of fibrinogen (70-100 mg/mL),5.22 and random-donor cryoprecipitate contains the lowest concentration (2.6-25 mg/mL).22*25Cryoprecipitate centrifugation methods result in concentrations of fibrinogen ranging from 21.6 to approximately 40 mg per mL.4.20 The repeat freeze-thaw centrifugation method of Wan et
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FIBRIN GLUE Table 1. Preparation methods for fibrin glue
Fibrinogen source Single-donor cryoprecipitate Single-donor fresh-frozen plasma Autologous whole blood sample Single-donor whole blood sample Single-donor cryoprecipitate Autologous whole blood sample Autologous whole blood sample Autologous whole blood sample Autologous or single-donor whole blood sample
Special modifications None Thaw plasma at 4°C Thaw plasma: no temperature given Thaw plasma 4-6°C Repeat freeze-thaw cycle Ammonium sulfate precipitation Ammonium sulfate precipitation Barium and magnesium sulfate; 30% PEG* Barium and magnesium sulfate: 30% PEG
Centrifugation speed and time
Fibrinogen content
Reference(s)
NA* 1000 x g , 15 min 4000 rpm, 10 min
NGt 21.6 mg/mL NG
15-18 4 19
6500 x g , 5 mln 4200 rpm, 12 rnin
40 mg/mL 40-59 mg/3-5 mL
20 22
3000 rpm, 5 mln
NG
10
3200 rpm, 3 min
NG
11
10,000 x g , 20 mln
NG
23
8000 rpm, 10 min
13.4-47.5 mg/mL 57-85 mg/mL
5 25
* Not applicable. t Not given.
t Polyethylene glycol.
al.zz results in reported fibrinogen yields of 40 to 58.5 mg per mL. Fibrinogen quantitation was carried out only in investigations using PEG precipitation. These reports revealed an average fibrinogen level of 31.8 mg per mL5 and a range between 57 and 85 mg per mL.= With the exception of routine cryoprecipitate methods and the centrifugation method described by Spotnitz et a1.,20 all other methods of concentration rely on preparation in open test tube systems. Because these opentube products were often stored for extended periods of time at refrigerator or freezer temperatures, the methods do not meet the requirements under the Code of Federal RegulationszGfor closed-system preparation of cryoprecipitate or the requirements of the American Association of Blood Banksz7 for open-system storage of blood products. To date, experimental data suggest that the fibrinogen content of the fibrin glue product is critical to the glue's tensile or adhesive strength.zz~Z8~z9 While commercially prepared fibrin glue preparations appear to provide uniform, maximum tensile strength as a result of their high fibrinogen content, some investigators have been able to approximate these results through modifications in cryoprecipitate preparation methods or through the use of precipitation The thrombin content of fibrin glue affects the rapidity of hemostasis and plays a major role when the hemostatic and sealing properties of the glue are the most important clinical c o n ~ i d e r a t i o n Clot . ~ ~ formation in less than 5 seconds can be induced by thrombin concentrations of 500 NIH units. Conversely, the process can be slowed from 30 seconds to several minutes by use of thrombin at levels of 4 NIH units.'B2 A dichotomy exists between the sealing and adhesive properties of the glue.
Current evidence suggests that increased thrombin levels actually lower the tensile strength of the fibrin The use of aprotinin in the sealant system remains controversial. Many United States authors have suggested that its addition is u n n e c e ~ s a r y ,but ~ ~other ~~~~~ published data have suggested that the incorporation of an antifibrinolytic agent promotes a seal that persists for 2 to 4 weeks, rather than only several d a y ~ . ~ JInl certain sites, such as the middle ear, rapid lysis of the sealant However, in surgical proceappears to be de~irab1e.I~ dures conducted on tissues with known high levels of fibrinolysins (e.g., lung, kidney, prostate, uterus), the inclusion of antiplasmins may be desirable.2J Adverse effects of the use of fibrin glue products (other than their potential for disease transmission) appear to be rare. Thrombosis secondary to the inadvertent intravascular administration of fibrin glue theoretically is possible. W o l n e P and Lupinetti et aI.l7 cite the theoretical risk of the introduction of the material into the circuit of the cardiopulmonary bypass pump, but do not report having encountered this problem. It is interesting that the application of fibrin glue onto vascular graft materials does not appear to be associated with increased evidence of intravascular thrombosis. In fact, Haverich et al.33 noted that fibrin glue-treated grafts are no more thrombogenic, and may actually be less thrombogenic, than untreated graft material or grafts pretreated with blood. The formation of adhesions in association with fibrin glue application would appear to be a possible outcome, but reports in the literature are relatively rare. Spotnitz et al.34 failed to demonstrate the presence of mediastinal fibrosis or inflammation 1 month after fibrin glue application in an animal model. McCarthy et al.j5 and Gold-
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GIBBLE AND NESS
man et aL3'j used either topical application or instillation of fibrin glue to repair experimental pleural injuries in laboratory animals. Both groups initially noted adhesion formation, but the adhesions appeared to resolve in 4 to 6 months. Harris et al.31 also reported a lack of reaction to fibrin glue or thrombin when these materials were injected into the middle ear of Sprague-Dawley rats. The lack or apparent resolution of tissue reaction with fibrin glue products may be related to the fibrinolysis and ultimate removal of the material from these tissue sites. In some cases, however, excess application of glue material may impede tissue repair. The interposition of glue between opposed nerve bundles has been observed to impede nerve regeneration, and the material also appears to limit bone repair and new bone formation in experimental bone t r a n ~ p l a n t a t i o n . ~ ~ . ~ ~ Clinical Applications Numerous reports concerning the application of fibrin glue can be found, particularly in the European literature, although studies in animal models and in human subjects (with cryoprecipitate-based glue methods) have also been reported from the United States. Studies reviewing experience in human subjects often fail to compare fibrin glue-treated groups with control groups. Although a few of these reports are anecdotal in nature, several involve large treatment groups of 100 or more patients and contrast clinical impressions with known past experiences. Conversely, animal experiments often involve the use of control groups with small numbers of individuals. Despite considerable variation in experimental design, studies have generally shown fibrin sealant systems to be efficacious in controlling slowly bleeding foci, diffuse oozing, bleeding from needle puncture sites, lymphatic leaks, serous fluid collections, and diffuse parenchymal organ hemorrhage. Fibrin glue does not control rapid arterial or venous hemorrhage and does not replace good surgical technique. We here cite general trends of fibrin glue application in various surgical specialities, and Table 2 supplies additional data concerning study design and outcome. Fibrin glue has found its most extensive application in the field of cardiothoracic and general vascular surgery. In cardiac surgery, fibrin glue has been successfully used to seal the foci of microvascular bleeding (from anastomoses and needle puncture sites), in prosthetic valve implantation, and in reducing mediastinal drainage, by spray application prior to chest c 1 0 s u r e . ~ ~Direct J~ application of the fibrin glue to synthetic vascular grafts has resulted in better sealing of graft materials than that achieved with older methods, such as whole blood or albumin re treatment.^^ Fibrin glue application has also, through its superior sealing properties, promoted the use
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of the more flexible woven dacron and knitted graft material^.^^,^^
In thoracic surgery, excellent results have been reported in the repair of pulmonary air leak35 and experimental pneumothorax"'j in two small animal studies. Kram et al.41 also used an animal model to examine tracheal sealing after experimental laceration. Surgical repair was limited to localized suturing with topical fibrin glue application, and good repair and outcome were reported in all subjects. Jessen and Sharma42 reviewed a n unusual application of the material, in the control of bronchial fistulas in five human subjects. Several of those patients had experienced chronic fistula formation that was resistant to alternative therapies, including irradiation. Successful fistula closure was noted in every patient, although repeated application was necessary in several cases. In the fields of trauma and transplant surgery, fibrin glue methods have been used with some success in posttraumatic splenic and liver salvage in both animal models and human s u b j e ~ t s . ~ ~Interest - ~ ' j in splenic salvage has recently been stimulated by the recognition of the increased incidence of postsplenectomy sepsis in some pat i e n t ~ . ~Scheele ~ * ~ ~et, al.43 ~ ~ examined splenic repair in over 100 human subjects and reported splenic salvage rates of 87 percent in patients with incidental splenic lesions and 60 percent in trauma patients. The lower rate of success in the trauma group was attributed to lack of experience with the sealant system. A control group was not described. Kram et a1.44,46investigated the repair of traumatic splenic and liver injuries in a dog model and reported a success rate exceeding that of Scheele et al.43 This outcome may have been related to the more controlled circumstances of the injuries and the smaller number of subjects involved in the studies. Margarit et al.48 used fibrin glue in the transplantation of partial hepatectomy specimens into an animal model. They examined various hemostatic agents and concluded that fibrin glue in combination with collagen felt provided the best degree of operative hemostasis in their experimental system. Fibrin glue would appear to be ideal for the reapplication of cutaneous and subcutaneous tissues in both plastic repair and general surgery. However, whereas reported results have generally been favorable, limitations of the glue technique have also been cited. In general, fibrin glue allows the close application of skin graft material, particularly over areas of contour complexi t y . ' ~In~ their ~ investigation of experimental radical neck dissection in rats, Lindsey et al.50 also noted that the application of fibrin glue appeared to prevent the formation of postoperative seromas. However, Ellis and Pelause' found fibrin glue to be ineffectual in tissue fixation during salivary gland procedures, and Jonk et al.51
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FIBRIN GLUE Table 2. Potential clinical applications of fibrin adhesives
Surgical field of use Cardiovascular
Thoracic Trauma Transplant Plastic repair Head and neck Oral Central nervous system, netve repair Gastrointestinal Orthopedic
Type of application
Reference(s)
Sealing of vascular anastomoses, prostheses, patches, and epicardial bleeding Mediastinal spray application Control of bleeding with vascular graft material Control of pneumothorax or pulmonary air leak Realignment of tracheal transection injury Treatment of bronchopleural fistula Repair of splenic injury Repair of liver laceration Transplant of partial hepatectomy specimen Fixation of skin grafts and flaps, blepharoplasty, brow and face lifts Seroma prevention in radical neck dissection Flap and graft procedures; tooth extraction in factor-deficient and anticoagulated patients Adjuvant to repair of dural injury; repair of peripheral nerve injury Repair common bile duct injury; adjuvant to repair of bowel anastomoses (possible) Repair of osteochondral fracture or Achilles tendon, orthopedic repair in hemophilia
32, 40
noted that the use of fibrin glue failed to prevent the postmastectomy formation of seromas in human subjects. The use of fibrin glue was first described in oral and maxillofacial surgery, and many reports of its successful application in this field continue to appear. Matrass2 summarized extensive applications of fibrin sealant in this type of surgery, and Pini Prato et al.53 compared the use of a commercial glue system to traditional suture repair for flap and graft placement in periodontal surgery. Fibrin sealant resulted in decreased operative time and hematoma formation and improved healing. Baudo et al.s4 demonstrated a decreased need for postoperative factor therapy in hemophiliacs and anticoagulated patients undergoing tooth extraction. In neurosurgical procedures, fibrin glue repair has been variably successful for dural sealing and peripheral nerve repair. In her extensive review article, M a t r a ~cited ~~a good outcome with the use of fibrin glue in maxillofacial nerve repair and in dual repair following traumatic injury and tumor surgery. In contrast, Nishihira et al.55 found that fibrin glue sealing alone was often insufficient in preventing the recurrence of experimental cerebrospinal rhinorrhea. In his review, N a r a k a ~addressed ~~ the problems encountered with the use of fibrin glue in peripheral nerve repair, including excess glue application and proper nerve fiber alignment. Despite those problems, he felt that fibrin glue played an important role in nerve repair. In some surgical disciplines, such as colonic and small bowel surgery, the use of fibrin glue remains extremely controversial or has restricted application. Kjaergaard et al.56 found sealant systems useful in sutureless colonic anastomoses in dogs. The authors noted no significant difference between the measured in vivo bursting pres-
34
39, 40 35, 36 41 42 43,44 45, 46 48 1,49 50 53,54 55,37 58, 56, 57
30
sure of sutured and nonsutured anastomotic sites. In direct contrast, Houston and Rotsteins7 noted an increased incidence of anastomotic leakage, abscess formation, and lowered anastomotic bursting pressure when fibrin glue was used in a rat model. It is interesting that Kram et al.58 noted a good outcome following repair of common duct anastomosis with fibrin glue and limited-stay sutures in animal models. The relatively good outcome noted in their series might have been related to the lower intraluminal pressures generated in the biliary duct system rather than in the small or large bowel. Orthopedic surgeIy is another field in which controversy persists as to the use of fibrin glue. Clear indications and good success have been noted in patients who undergo osteochondral fracture fixation and repair of ruptured Achilles tendon and in hemophiliacs who undergo orthopedic surgery;30 however, the influence of the material on general bone growth and repair remains uncertain. Lucht et al.38 studied the effect of combining fibrin glue with autologous bone chips for the repair of bony tibia1 defects. Fibrin glue-treated bone sites exhibited less formation of new bone than sites repaired with autologous bone chips alone. These findings contrast with the enhancing effect that fibrin glue appears to have on healing at other tissue sites and suggest that other factors may be operative at sites of bony repair. Conclusions
Despite the restrictions of fibrin glue usage in some surgical fields, clinical and experimental evidence suggests that fibrin glue has the potential for wide applicability as a surgical hemostatic and adhesive agent. In
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GIBBLE AND NESS
general, the application of fibrin glue has been restricted in the United States, because of lack of familiarity with the material and inexperience in its use. The lack of availability of commercially manufactured glue products undoubtedly has also played a role in the underutilization of the material in this country. This is unfortunate, in view of the fact that there are many currently available methods for preparation of fibrin glue, from both autologous and single-donor homologous sources. Singledonor-derived products supply sufficient quantities of fibrin glue for most types of surgical procedures, and the fibrinogen levels in these products are generally adequate for achieving operative hemostasis. Several fibrin glue production methods result in fibrinogen concentrations that approach the levels found in commercial products. These methods appear to supply sufficient fibrinogen for tissue adhesion and bonding when those processes are c r i t i ~ a l . ~ ~Moreover, - ~ ~ . ~ ’ the use of an autologous source for fibrin glue is ideal because of the lack of risk of disease transmission by this type of product. Finally, institutional development of protocols for fibrin glue production should be encouraged, because these materials actually appear to reduce the need for blood products in some patients.34 Whereas the production of single-donor fibrin glue may meet the current need for this product in the United States at the present time, a decision clearly must be made as to whether carefully prepared commercial fibrin glue products are worth the risk. What information would be helpful in making this decision? First, it is evident that many reports on the use of commercial glue products in humans are anecdotal and often fail to use adequate control groups for comparison purposes. Animal experiments generally are better designed, but their applicability to similar human surgical procedures remains uncertain. Carefully designed studies that demonstrate a clear benefit from fibrin glue application would undoubtedly make the decision about the use of this material easier. Second, questions about viral infectivity still remain as a central concern with commercial products. Current evidence suggests that the potential for viral exposure through the use of these agents is small, and in fact, this risk may be less than that of receiving multiple additional blood products to achieve operative hemostasis. Developing technologies in the fractionation industry may make these risks even smaller. Some potential methods for lessening the risk of virus transmission include the application of solvent-detergent purification methods, modified heat treatment, or monoclonal antibody purification techniques to the manufacture of fibrin glue.12 These strategies may ultimately make this valuable product available in the United States, although such availability is undoubtedly at least several years away. Until safe commercial products become available, however,
the use of fibrin glue-preferably from autologous and single-donor sources-should be strongly encouraged by the blood banking community. References 1. Ellis DAF, Pelausa EO. Fibrin glue in facial plastic and rcconstructive surgery. J Otolaryngol 1988;17:74-7. 2. Matras H. Fibrin seal: the state of the art. J Oral Maxillofac Surg 1985;43:605-11. 3. Kram HB, Nathan RC, Mackabee JR, Klein SR, Shoemaker WC. Clinical use of nonautologous fibrin gluc. Am Surg 1988:54:570-3. 4. Drcsdale A, Rose EA, Jeevanandam V, Recmtsma K, Bowman FO, Malm JR. Preparation of fibrin gluc from single-donor freshfrozen plasma. Surgery 1985:97:750-5. 5 . Weisman RA, Torsiglicri AJ, Schreibcr AD, Epsfcin GH. Biochemical characterization of autologous fibrinogen adhesive. Laryngoscope 1987;97:1186-90. 6. Matras H, Dinges HP, Lassmann H, Mamoli B. (Suturc-frcc interfascicular ncwe transplantation in animal cxperiments] (Ger) Wicn Med Wochenschr 1972;122:517-23. 7. Bovc JR. Fibrinogcn-is thc benefit worth the risk? Transfusion 1978;19:129-36. 8. Petcrsen JK. Clinical experience in oral surgery with human fibrin sealant. Int Dent J 1985;35:277-9. 9. Schelling G, Block T, Coke1 M, Blankc E, Hammer C, Brcndcl W. Application of a fibrinogen-thrombin-collagen-based hcmostyptic agent in experimental injuries of liver and splecn. J Trauma 1988;28:472-5. 10. Durham LH, Willatt DJ, Yung MW, Jones I, Stevenson PA, Ramadan MF. A method for prcparation of fibrin gluc. J Laryngol Otoi 1987;101:1182-6. 11. Sicdentop KH, Harris DM, Ham K, Sanchez B. Extended experimental and preliminary surgical findings with autologous fibrin tissue adhesive made from patient’s own blood. Laryngoscope 1986;96: 1062-4. 12. Clark DB, Drohan WN, Miekka SI, Katz AJ. Strategy for purification of coagulation factor concentrates. Ann Clin Lab Sci 1989; 19: 196-207. 13. Cain JE, Dryer RF, Barton BR. Evaluation of dural closure techniques. Suture methods, fibrin adhesive sealant, and cyanoacrylate polymer. Spine 1988;13:720-5. 14. Hilfenhaus J, Weidmann E. Fibrin glue safety: inactivation of potential viral contaminants by pasteurization of thc human plasma componcnts. Arzneimittelforschung 1985;35:1617-9. 15. Moront MG, Katz NM, O’Connell J, Hoy GR. The use of topical fibrin gluc at cannulation sites in nconatcs. Surg Gynecol Obstct 1988;166:358-9. 16. Kennedy JG, Saundcrs RL. Usc of cryoprccipitatc coagulum 10 control tumor-bcd bleeding. Case report. J Neurosurg 1984;60:1099-
101. 17. Lupinefti FM, Stoncy WS, Alford WC, ct al. Cryoprccipitatctopical thrombin gluc. Initial expcriencc in patients undcrgoing cardiac operations. J Thorac Cardiovasc Surg 1985;90:502-5. 18. Rousou JA, Engclman RM, Breyer RH. Fibrin gluc: a n cffective hemostatic agent for nonsuturablc intraoperafivc blccding. Ann Thorac Surg 1984;38:409-10. 19. Moretz WH Jr, Shea JJ Jr, Emmett JR, Shca JJ 111. A simple autologous fibrinogen glue for ofologic surgcry. Otolaryngol Head Neck Surg 1986;95:122-4. 20. Spotnitz WD, Mintz PD, Avcry N, Bithcll TC, Kaul S , Nolan SP. Fibrin glue from stored human plasma. An inexpcnsive and efficient mcfhod for local blood bank prcparation. Am Surg 1987;53:460-2. 21. Dresdale A, Bowman FO, Malm JR, et al. Hcmostatic cffccfivcness of fibrin glue derived from singlc-donor frcsh frozcn plasma. Ann Thorac Surg 1985;40:385-7. 22. Wan HL, Huang ST, Floyd DM, McGowan EI, Feldman DS. Is the amount of fibrinogen in cryoprccipitate adequate for fibrin glue? Introducing an improved recycled cryoprccipitatc mcthod (abstract). Transfusion 1989;29(Suppl):41S.
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23. Feldman MD, Sataloff RT, Choi HY, Ballas SK. Compatibility of autologous fibrin adhesivc with implant materials. Arch Otolaryngol Head Neck Surg 1988;114:182-5. 24. Sicdentop KH, Harris DM, Sanchez B. Autologous fibrin tissue adhesive. Laryngoscope 1985;95:1074-6. 25. Silberstcin LE, Williams LT,Hughlctt MA, Magec DA, Weisman RA. An autologous fibrinogen-based advcsive for use in otologic surgery. Transfusion 1988;28:319-21. 26. 21 CFR 5 640.50. 27. Holland PV, Schmidt PJ, cds. Standards for blood banks and transfusion services. 12th ed. Arlington: American Association of Blood Banks, 1987:B4110. 28. Marshall S. Commercial fibrinogen, autogenous plasma, whole blood and cryoprecipitate for coagulum pyelolithotomy: a comparative study. J Urol 1978;119:310-1. 29. Siedcntop KH, Harris DM, Sanchez B. Autologous fibrin tissue adhesive: factors influencing bonding power. Laryngoscope 1988;98:731-3. 30. Schlag G, Rcdl H. Fibrin sealant in orthopedic surgery. Clin Orthop 1988;227:269-85. 31. Harris DM, Sicdcntop KH, Ham KR, Sanchez B. Autologous fibrin tissue adhcsivc biodcgration and systcmic effects. Laryngoscope 1987;97: 1141-4. 32. Wolner E. Fibrin gluing in cardiovascular surgery. Thorac Cardiovasc Surg 1982;30:236-7. 33. Haverich A, Walterbusch G, Borst HG. The use of fibrin glue for sealing vascular prostheses of high porosity. Thorac Cardiovasc Surg 1981;29:252-4. 34. Spotnitz WD, Dalton MS, Baker JW, Nolan SP. Reduction of perioperative hemorrhage by anterior mediastinal spray application of fibrin gluc during cardiac operations. Ann Thorac Surg 1987;44:529-31. 35. McCarthy PM, Trastek VF, Bell DG, et al. The effectiveness of fibrin glue sealant for reducing experimental pulmonary air leak. Ann Thorac Surg 1988;45:203-5. 36. Goldman CD, Blocker SH, Ternberg JL, Crouch EC. Management of experimental pncumothorax in weanling rabbits with the use of fibrin glue sclerosant. Arch Surg 1986;121:565-8. 37. Narakas A. The use of fibrin glue in repair of peripheral nerves. Orthop Clin North Am 1988;19:187-99. 38. Lucht U, Biinger C, Maller JT, Joyce F, Plcnk H Jr. Fibrin sealant in bone transplantation. No effects on blood flow and bone formation in dogs. Acta Orthop Scand 1986;57:19-24. 39. Gundry SR, Behrendt DM. A quantitative and qualitative comparison of fibrin glue, albumin, and blood as agcnts to pretrcat porous vascular grafts. J Surg Res 1987;43:75-7. 40. Borsf HG, Haverich A, Walterbusch G, Maatz W. Fibrin adhcsive: an important hemostatic adjunct in cardiovascular operations. J Thorac Cardiovasc Surg 1982;84:548-53. 41. Kram HB, Shoemakcr WC, Hino ST, Chiang HS, Harley DP, Flcming AW. Trachcal rcpair with fibrin glue. J Thorac Cardiovasc Surg 1985;90:771-5.
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42. Jessen C, Sharma P. Use of fibrin glue in thoracic surgery. Ann Thorac Surg 1985;39:521-4. 43. Scheele J, Gentsch HH, Mattcson E. Splenic repair by fibrin tissue adhcsive and collagen flcece. Surgery 1984;95:6-13. 44. Kram HB, Shoemaker WC, Hino ST, Harley DP. Splenic salvage using biologic glue. Arch Surg 1984;119:1309-11. 45. Blocker SH, Ternberg JL. Traumatic livcr laceration in the newborn: repair with fibrin gluc. J Pediatr Surg 1986;21:369-71. 46. Kram HB, Reuben BI, Fleming AW, Shoemakcr WC. Usc of fibrin glue in hepatic trauma. N Trauma 1988;28:1195-201. 47. Masur H, Fauci AS. Infections in the compromised host. In: Braunwald E, Isselbachcr KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal rncdicinc. 11th ed. New York: McGraw-Hill, 1987:469. 48. Margarit C, Martinez-lb6iez V, Lloret J, ct al. Segrncntal livcr transplantation in pigs: use of a fibrin scalant and collagen as hemostatic agents. Transplant Proc 1987; 19:3835-7. 49. Lilius P. Fibrin adhcsivc: its use in selected skin grafting. Practical note. Scdnd J Plast Reconstr Surg Hand Surg 1987;21:245-8. 50. Lindsey WH, Masterson TM, Llancras M, Spotnitz WD, Wancbo HJ, Morgan RF. Scroma prcvcntion using fibrin glue during modified radical neck disscction i n a rat modcl. A m J Surg 1988;156:310-3. 51. Jonk A, van Dongen JA, Kroon BBR. Prcvcntion of scroma following axillary lymph node dissection or radical mastectomy; ineffectiveness of fibrin glue sealing techniquc (lertcr). Neth J Surg 1987;39:135. 52. Mafras H. The use of fibrin sealant in oral and maxillofacial surgery. J Oral Maxillofac Surg 1982;40:617-22. 53. Pini Prato GP, Cortellini P, Agudio G, Clauser C. Human fibrin glue versus sutures in periodonfal surgery. J Periodontol 1987;58:426-31. 54. Baudo F, deCataldo F, Landonio G, Muti G. Managcrnent of oral bleeding in haemophilic patients (letter). Lancet 1988;2:1082. 55. Nishihira S, McCaffrey TV.The use of fibrin glue for the repair of experimental CSF rhinorrhea. Laryngoscope 1988;98:625-7. 56. Kjacrgaard J, Nordkild P, Sjmtoft E, Hjorrrup A. Non-suturcd fibrin adhesive vs. sutured anastomosis. A comparativc inrra-individual study in dog colon. Acta Chir Scand 1987;153:599-601. 57. Houston KA, Rotstein OD. Fibrin scnlant in high-risk colonic anastomoses. Arch Surg 1988;123:230-4. 58. Kram HB, Garces MA, Klein SR, Shoemaker WC. Conlmon bilc duct anastomosis using fibrin glue. Arch Surg 1985;120:1250-6.
Joan W. Gibble, MD, Associate Medical Director of Blood Scrvices, American Red Cross Blood Scrviccs, Chesapeake Region, 4700 Mount Hope Drive, Baltimore, MD 21215. [Reprint rcqucsts] Paul M. Ness, MD, Dircctor of the Blood Bank, Johns Hopkins Hospital , Baltimore, MD, and Executive Dircctor of Blood Services, Amcrican Red Cross Blood Services, Chcsapcake Region.
Fibrin glue: the perfect operative sealant? J.W. GIBBLEA N D P.M. NESS
DESPITETHE DEVELOPMENT OF modern surgical techniques and improvements in intraoperative hemostasis, the search for the perfect hemostatic agent continues.’ Technologic advances have included improved suture materials, metallic staples and clips, and a variety of natural and synthetic hemostatic agents including collagen products (i.e., collagen fleece), absorbable gelatin sponges, oxidized cellulose, and synthetic cyanoacrylate-based glues. Fibrin glue (fibrin sealant) has been advocated by many surgeons as the material that best approaches the ideal operative sealant. Abundant reports have appeared, touting its beneficial properties. As a naturally occurring and partially human-derived product, the material appears to have no tissue toxicity, promotes a firm seal in seconds to minutes, is reabsorbed in days to weeks following application, and appears to promote local tissue growth and r e ~ a i r . The ~ . ~ use of this material outside of the United States, particularly in Europe, has flourished. Its use within the United States has lagged more than a decade behind that in Europe, largely because of the lack of ready access to commercially prepared material^.^ The rationale for the exclusion of commercially prepared products from the United States market will be examined in this article. We will also review the development of fibrin glue, its composition and mechanism of action, alternatives to commercial products, and current indications for the use of this material. Historical Perspective
Interest in the use of fibrinogen as a natural surgical adhesive began the early 1 9 0 0 and ~ ~ there was additional experimentation in the 1940s. As detailed by MatrasY2 early studies concentrated on the direct application of fibrin powder or fibrin tampons to bleeding surfaces. Later, more sophisticated attempts used a fibrinogenthrombin clotting system to anchor skin grafts. In general, the adhesive qualities of these preparations were poor. Most authors2.’ have cited a lack of a concentrated source of fibrinogen as the reason for the suboptimal adhesive properties used in these early experiments. The From [he Amcrican Rcd Cross, Blood Scrvices, Chcsapcakc Rcgion, Baltimorc, Maryland, and thc Johns Hopkins School of Mcdicine Baltimorc. Reccived for publication Sepfembcr 6 , 1989; revision received January 29, 1990, and accepted March 12, 1990.
741
concept of a fibrin sealant system became a reality in the early 1970s, when techniques for the isolation and concentration of clotting factors were improved. In 1972, Matras et al.6 described the successful application of a fibrin glue system for peripheral nerve repair. Their method is similar to modern commercial systems of fibrin glue application. Since the time of that study, numerous articles investigating and expanding the potential applications of fibrin glue have appeared in the world literature. Because fibrin glue methods depend on a consistent and concentrated source of human fibrinogen, investigation in the United States was largely halted in 1978 when the Food and Drug Administration revoked the license for the clinical use of pooled commercial fibrinogen concentrates. This ban, which was based on the well-recognized observation of the high risk of hepatitis transmission by f i b r i n ~ g e n ,eliminated ~ the importation into the United States of commercially prepared fibrin glue systems. Such products currently available in Europe include Tisseel (Immuno, Vienna, Austria) and Beriplast (Behringwerke AG, Marburghhn, FRG). Their advantages are ready availability and consistent provision of a source of fibrinogen and other constituents. Standardized manufacturing processes ensure an acceptable product with increased likelihood of uniform performance in the surgical field. Plasma- and cryoprecipitate-based methods for the production of fibrin glue (for individual patients) have been developed in the United States, but the use of fibrin glue remains limited here, because these methods are viewed as time-consuming, cumbersome, and unpredictable. Components and Mechanism of Action
The mechanism of the fibrin glue system mimics the final stage of the coagulation cascade, in which fibrinogen is converted to fibrin in the presence of thrombin, factor XI11 (FXIII), fibronectin, and ionized calcium. The Tisseel fibrin sealant system allows this reaction to be examined in greater depth. The kit consists of a vial of lyophylized concentrated fibrinogen that also contains fibronectin, FXIII, and reduced amounts of plasminogen. The concentrate is reconstituted with a solution containing aprotinin, which is a bovine-derived protease inhibitor with antifibrinolytic activity, the addition of which theoretically enhances the persistence of the fibrin
742
GIBBLE AND NESS
clot or seal. (Studies to date do seem to support this concept.) The fibrinogen and aprotinin solutions are combined, mixed thoroughly, and warmed to 37°C. The second component of the kit, bovine thrombin, is reconstituted with a calcium chloride solution. The thrombin is present in the kit in concentrations of 4 and 500 NIH units, and the concentration can be selected for slower (4 NIH units) or faster (500 NIH units) clotting, as needed. Application is usually carried out with a double-barreled syringe apparatus (Dupolject, Immuno), which allows for simultaneous application through a blunt-tipped needle of equal amounts of the fibrinogen and thrombin solutions. Alternatively, the materials can be applied by spray application with forced sterile gas, by mixing equal proportions of the solutions on application. Although not as effective as these equal mixing techniques, sandwich applications of the materials (a layer of fibrinogen solution followed by a layer of thrombin solution) have been successful in oral surgical procedures and for the application of collagen fleece to wound surfaces.2.8 The reaction proceeds by thrombin cleavage of fibrinopeptides A and B from the fibrinogen molecule, which results in the formation of fibrin monomers. Thrombin also activates FXIII, which in turn allows for stable fibrin cross-linkage (in the presence of ionized calcium) and the formation of a firm, nonfriable clot. Fibronectin is also a participant in fibrin cross-linkage, and its inclusion in the fibrin glue system appears to promote cellular migration and fibroblastic growth into areas of fibrin seal application.2 A modification of the basic fibrin sealant system includes the incorporation of the kit materials into layered collagen fleece (FTCH, Hormon-Chemie, Munich, FRG). The fibrinogen-to-fibrin conversion is promoted by application to wet tissue surfaces, which brings the incorporated thrombin in contact with f i b r i n ~ g e n . ~ Alternatives to Commercial Fibrin Glue
The risk of virus transmission by commercial fibrin glue products is still debated. Theoretically, viruses remaining in these topical preparations could be adsorbed and retained by the patient, which could result in the transmission of hepatitis B, non-A,non-B hepatitis, HIV-1, and possibly other blood-borne viruses, such as HIV-2. However, much literature reports the absence of documented cases of virus transmission after the use of fibrin glue p r o d u ~ t s . * ~ Ca' ~ ~i n' ~et- ~al.I3 ~ summarized several European studies that failed to show evidence of disease transmission in over 1 million patients who underwent operations in which commercial fibrin glue was used. The general absence of such virus transmission appears to be due to careful donor selection, extensive virologic and alanine aminotransferase (ALT) testing,
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and heat treatment of these products.'J4 Despite these intensive efforts to eliminate disease risk, many investigators seem to retain some doubt as to the safety of these products. Restricted access to European commercial fibrin sealant systems has resulted in the investigation of alternative fibrinogen sources in the United States. Many of these studies have relied on autologous or single-donor cryoprecipitate as a source of f i b r i n ~ g e n . ~ . ' ~Autolo-~' gous-source fibrinogen eliminates the risks of virus transmis~ion.'~Although single-donor and autologous cryoprecipitate methods produce limited amounts of fibrinogen concentrate, the yields are usually sufficient for most types of operative procedure. However, the use of autologous blood units or samples necessitates preoperative planning, and those products are not generally available for emergency therapy. Single-donor cryoprecipitate methods have been more widely applied, as the cryoprecipitate is readily available, and the associated risk of viral disease transmission is equivalent to that with transfusion of single-donor blood products. In the simplest terms, cryoprecipitate methods combine the direct application of thawed cyroprecipitate to the bleeding surface and the application of bovine topical thrombin (usual concentration, 1000 units/mL). 15-18 The clotting reaction is enhanced when thrombin is reconstituted with calcium ~ h l o r i d e . ' ' . ~As ~ a rule, antifibrinolytic agents such as aprotinin are not included in these cyroprecipitate-thrombin glue mixtures. The significance of this omission will be reviewed shortly. Modifications of the basic cryoprecipitate method described above (see Table 1) include the addition of a centrifugation step to concentrate further the precipitated fibrin~gen.~.'"~'In these studies, centrifugation speeds and times ranged from 1000 x g for 15 minutes to 6500 x g for 5 minute^.^.^^ Wan et a1.22 combined a repeat freeze-thaw cycle with centrifugation (4200 rpm) and complete plasma drainage to enhance fibrinogen yields. Other investigators used chemical additives to increase fibrinogen yields. Such methods included ammonium sulfate precipitation or the addition of polyethylene glycol (PEG).5.'0.23-25Durham et al.'O and Seidentop et suggested the safety of ammonium sulfate precipitation methods for in vivo use. Weisman et al.' and Silberstein et al.2' demonstrated the efficacy and safety of PEG methods for topical applications in the middle ear. Comparative studies have shown that the commercially prepared Tisseel product generally contains the highest concentration of fibrinogen (70-100 mg/mL),5.22 and random-donor cryoprecipitate contains the lowest concentration (2.6-25 mg/mL).22*25Cryoprecipitate centrifugation methods result in concentrations of fibrinogen ranging from 21.6 to approximately 40 mg per mL.4.20 The repeat freeze-thaw centrifugation method of Wan et
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743
FIBRIN GLUE Table 1. Preparation methods for fibrin glue
Fibrinogen source Single-donor cryoprecipitate Single-donor fresh-frozen plasma Autologous whole blood sample Single-donor whole blood sample Single-donor cryoprecipitate Autologous whole blood sample Autologous whole blood sample Autologous whole blood sample Autologous or single-donor whole blood sample
Special modifications None Thaw plasma at 4°C Thaw plasma: no temperature given Thaw plasma 4-6°C Repeat freeze-thaw cycle Ammonium sulfate precipitation Ammonium sulfate precipitation Barium and magnesium sulfate; 30% PEG* Barium and magnesium sulfate: 30% PEG
Centrifugation speed and time
Fibrinogen content
Reference(s)
NA* 1000 x g , 15 min 4000 rpm, 10 min
NGt 21.6 mg/mL NG
15-18 4 19
6500 x g , 5 mln 4200 rpm, 12 rnin
40 mg/mL 40-59 mg/3-5 mL
20 22
3000 rpm, 5 mln
NG
10
3200 rpm, 3 min
NG
11
10,000 x g , 20 mln
NG
23
8000 rpm, 10 min
13.4-47.5 mg/mL 57-85 mg/mL
5 25
* Not applicable. t Not given.
t Polyethylene glycol.
al.zz results in reported fibrinogen yields of 40 to 58.5 mg per mL. Fibrinogen quantitation was carried out only in investigations using PEG precipitation. These reports revealed an average fibrinogen level of 31.8 mg per mL5 and a range between 57 and 85 mg per mL.= With the exception of routine cryoprecipitate methods and the centrifugation method described by Spotnitz et a1.,20 all other methods of concentration rely on preparation in open test tube systems. Because these opentube products were often stored for extended periods of time at refrigerator or freezer temperatures, the methods do not meet the requirements under the Code of Federal RegulationszGfor closed-system preparation of cryoprecipitate or the requirements of the American Association of Blood Banksz7 for open-system storage of blood products. To date, experimental data suggest that the fibrinogen content of the fibrin glue product is critical to the glue's tensile or adhesive strength.zz~Z8~z9 While commercially prepared fibrin glue preparations appear to provide uniform, maximum tensile strength as a result of their high fibrinogen content, some investigators have been able to approximate these results through modifications in cryoprecipitate preparation methods or through the use of precipitation The thrombin content of fibrin glue affects the rapidity of hemostasis and plays a major role when the hemostatic and sealing properties of the glue are the most important clinical c o n ~ i d e r a t i o n Clot . ~ ~ formation in less than 5 seconds can be induced by thrombin concentrations of 500 NIH units. Conversely, the process can be slowed from 30 seconds to several minutes by use of thrombin at levels of 4 NIH units.'B2 A dichotomy exists between the sealing and adhesive properties of the glue.
Current evidence suggests that increased thrombin levels actually lower the tensile strength of the fibrin The use of aprotinin in the sealant system remains controversial. Many United States authors have suggested that its addition is u n n e c e ~ s a r y ,but ~ ~other ~~~~~ published data have suggested that the incorporation of an antifibrinolytic agent promotes a seal that persists for 2 to 4 weeks, rather than only several d a y ~ . ~ JInl certain sites, such as the middle ear, rapid lysis of the sealant However, in surgical proceappears to be de~irab1e.I~ dures conducted on tissues with known high levels of fibrinolysins (e.g., lung, kidney, prostate, uterus), the inclusion of antiplasmins may be desirable.2J Adverse effects of the use of fibrin glue products (other than their potential for disease transmission) appear to be rare. Thrombosis secondary to the inadvertent intravascular administration of fibrin glue theoretically is possible. W o l n e P and Lupinetti et aI.l7 cite the theoretical risk of the introduction of the material into the circuit of the cardiopulmonary bypass pump, but do not report having encountered this problem. It is interesting that the application of fibrin glue onto vascular graft materials does not appear to be associated with increased evidence of intravascular thrombosis. In fact, Haverich et al.33 noted that fibrin glue-treated grafts are no more thrombogenic, and may actually be less thrombogenic, than untreated graft material or grafts pretreated with blood. The formation of adhesions in association with fibrin glue application would appear to be a possible outcome, but reports in the literature are relatively rare. Spotnitz et al.34 failed to demonstrate the presence of mediastinal fibrosis or inflammation 1 month after fibrin glue application in an animal model. McCarthy et al.j5 and Gold-
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GIBBLE AND NESS
man et aL3'j used either topical application or instillation of fibrin glue to repair experimental pleural injuries in laboratory animals. Both groups initially noted adhesion formation, but the adhesions appeared to resolve in 4 to 6 months. Harris et al.31 also reported a lack of reaction to fibrin glue or thrombin when these materials were injected into the middle ear of Sprague-Dawley rats. The lack or apparent resolution of tissue reaction with fibrin glue products may be related to the fibrinolysis and ultimate removal of the material from these tissue sites. In some cases, however, excess application of glue material may impede tissue repair. The interposition of glue between opposed nerve bundles has been observed to impede nerve regeneration, and the material also appears to limit bone repair and new bone formation in experimental bone t r a n ~ p l a n t a t i o n . ~ ~ . ~ ~ Clinical Applications Numerous reports concerning the application of fibrin glue can be found, particularly in the European literature, although studies in animal models and in human subjects (with cryoprecipitate-based glue methods) have also been reported from the United States. Studies reviewing experience in human subjects often fail to compare fibrin glue-treated groups with control groups. Although a few of these reports are anecdotal in nature, several involve large treatment groups of 100 or more patients and contrast clinical impressions with known past experiences. Conversely, animal experiments often involve the use of control groups with small numbers of individuals. Despite considerable variation in experimental design, studies have generally shown fibrin sealant systems to be efficacious in controlling slowly bleeding foci, diffuse oozing, bleeding from needle puncture sites, lymphatic leaks, serous fluid collections, and diffuse parenchymal organ hemorrhage. Fibrin glue does not control rapid arterial or venous hemorrhage and does not replace good surgical technique. We here cite general trends of fibrin glue application in various surgical specialities, and Table 2 supplies additional data concerning study design and outcome. Fibrin glue has found its most extensive application in the field of cardiothoracic and general vascular surgery. In cardiac surgery, fibrin glue has been successfully used to seal the foci of microvascular bleeding (from anastomoses and needle puncture sites), in prosthetic valve implantation, and in reducing mediastinal drainage, by spray application prior to chest c 1 0 s u r e . ~ ~Direct J~ application of the fibrin glue to synthetic vascular grafts has resulted in better sealing of graft materials than that achieved with older methods, such as whole blood or albumin re treatment.^^ Fibrin glue application has also, through its superior sealing properties, promoted the use
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of the more flexible woven dacron and knitted graft material^.^^,^^
In thoracic surgery, excellent results have been reported in the repair of pulmonary air leak35 and experimental pneumothorax"'j in two small animal studies. Kram et al.41 also used an animal model to examine tracheal sealing after experimental laceration. Surgical repair was limited to localized suturing with topical fibrin glue application, and good repair and outcome were reported in all subjects. Jessen and Sharma42 reviewed a n unusual application of the material, in the control of bronchial fistulas in five human subjects. Several of those patients had experienced chronic fistula formation that was resistant to alternative therapies, including irradiation. Successful fistula closure was noted in every patient, although repeated application was necessary in several cases. In the fields of trauma and transplant surgery, fibrin glue methods have been used with some success in posttraumatic splenic and liver salvage in both animal models and human s u b j e ~ t s . ~ ~Interest - ~ ' j in splenic salvage has recently been stimulated by the recognition of the increased incidence of postsplenectomy sepsis in some pat i e n t ~ . ~Scheele ~ * ~ ~et, al.43 ~ ~ examined splenic repair in over 100 human subjects and reported splenic salvage rates of 87 percent in patients with incidental splenic lesions and 60 percent in trauma patients. The lower rate of success in the trauma group was attributed to lack of experience with the sealant system. A control group was not described. Kram et a1.44,46investigated the repair of traumatic splenic and liver injuries in a dog model and reported a success rate exceeding that of Scheele et al.43 This outcome may have been related to the more controlled circumstances of the injuries and the smaller number of subjects involved in the studies. Margarit et al.48 used fibrin glue in the transplantation of partial hepatectomy specimens into an animal model. They examined various hemostatic agents and concluded that fibrin glue in combination with collagen felt provided the best degree of operative hemostasis in their experimental system. Fibrin glue would appear to be ideal for the reapplication of cutaneous and subcutaneous tissues in both plastic repair and general surgery. However, whereas reported results have generally been favorable, limitations of the glue technique have also been cited. In general, fibrin glue allows the close application of skin graft material, particularly over areas of contour complexi t y . ' ~In~ their ~ investigation of experimental radical neck dissection in rats, Lindsey et al.50 also noted that the application of fibrin glue appeared to prevent the formation of postoperative seromas. However, Ellis and Pelause' found fibrin glue to be ineffectual in tissue fixation during salivary gland procedures, and Jonk et al.51
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FIBRIN GLUE Table 2. Potential clinical applications of fibrin adhesives
Surgical field of use Cardiovascular
Thoracic Trauma Transplant Plastic repair Head and neck Oral Central nervous system, netve repair Gastrointestinal Orthopedic
Type of application
Reference(s)
Sealing of vascular anastomoses, prostheses, patches, and epicardial bleeding Mediastinal spray application Control of bleeding with vascular graft material Control of pneumothorax or pulmonary air leak Realignment of tracheal transection injury Treatment of bronchopleural fistula Repair of splenic injury Repair of liver laceration Transplant of partial hepatectomy specimen Fixation of skin grafts and flaps, blepharoplasty, brow and face lifts Seroma prevention in radical neck dissection Flap and graft procedures; tooth extraction in factor-deficient and anticoagulated patients Adjuvant to repair of dural injury; repair of peripheral nerve injury Repair common bile duct injury; adjuvant to repair of bowel anastomoses (possible) Repair of osteochondral fracture or Achilles tendon, orthopedic repair in hemophilia
32, 40
noted that the use of fibrin glue failed to prevent the postmastectomy formation of seromas in human subjects. The use of fibrin glue was first described in oral and maxillofacial surgery, and many reports of its successful application in this field continue to appear. Matrass2 summarized extensive applications of fibrin sealant in this type of surgery, and Pini Prato et al.53 compared the use of a commercial glue system to traditional suture repair for flap and graft placement in periodontal surgery. Fibrin sealant resulted in decreased operative time and hematoma formation and improved healing. Baudo et al.s4 demonstrated a decreased need for postoperative factor therapy in hemophiliacs and anticoagulated patients undergoing tooth extraction. In neurosurgical procedures, fibrin glue repair has been variably successful for dural sealing and peripheral nerve repair. In her extensive review article, M a t r a ~cited ~~a good outcome with the use of fibrin glue in maxillofacial nerve repair and in dual repair following traumatic injury and tumor surgery. In contrast, Nishihira et al.55 found that fibrin glue sealing alone was often insufficient in preventing the recurrence of experimental cerebrospinal rhinorrhea. In his review, N a r a k a ~addressed ~~ the problems encountered with the use of fibrin glue in peripheral nerve repair, including excess glue application and proper nerve fiber alignment. Despite those problems, he felt that fibrin glue played an important role in nerve repair. In some surgical disciplines, such as colonic and small bowel surgery, the use of fibrin glue remains extremely controversial or has restricted application. Kjaergaard et al.56 found sealant systems useful in sutureless colonic anastomoses in dogs. The authors noted no significant difference between the measured in vivo bursting pres-
34
39, 40 35, 36 41 42 43,44 45, 46 48 1,49 50 53,54 55,37 58, 56, 57
30
sure of sutured and nonsutured anastomotic sites. In direct contrast, Houston and Rotsteins7 noted an increased incidence of anastomotic leakage, abscess formation, and lowered anastomotic bursting pressure when fibrin glue was used in a rat model. It is interesting that Kram et al.58 noted a good outcome following repair of common duct anastomosis with fibrin glue and limited-stay sutures in animal models. The relatively good outcome noted in their series might have been related to the lower intraluminal pressures generated in the biliary duct system rather than in the small or large bowel. Orthopedic surgeIy is another field in which controversy persists as to the use of fibrin glue. Clear indications and good success have been noted in patients who undergo osteochondral fracture fixation and repair of ruptured Achilles tendon and in hemophiliacs who undergo orthopedic surgery;30 however, the influence of the material on general bone growth and repair remains uncertain. Lucht et al.38 studied the effect of combining fibrin glue with autologous bone chips for the repair of bony tibia1 defects. Fibrin glue-treated bone sites exhibited less formation of new bone than sites repaired with autologous bone chips alone. These findings contrast with the enhancing effect that fibrin glue appears to have on healing at other tissue sites and suggest that other factors may be operative at sites of bony repair. Conclusions
Despite the restrictions of fibrin glue usage in some surgical fields, clinical and experimental evidence suggests that fibrin glue has the potential for wide applicability as a surgical hemostatic and adhesive agent. In
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GIBBLE AND NESS
general, the application of fibrin glue has been restricted in the United States, because of lack of familiarity with the material and inexperience in its use. The lack of availability of commercially manufactured glue products undoubtedly has also played a role in the underutilization of the material in this country. This is unfortunate, in view of the fact that there are many currently available methods for preparation of fibrin glue, from both autologous and single-donor homologous sources. Singledonor-derived products supply sufficient quantities of fibrin glue for most types of surgical procedures, and the fibrinogen levels in these products are generally adequate for achieving operative hemostasis. Several fibrin glue production methods result in fibrinogen concentrations that approach the levels found in commercial products. These methods appear to supply sufficient fibrinogen for tissue adhesion and bonding when those processes are c r i t i ~ a l . ~ ~Moreover, - ~ ~ . ~ ’ the use of an autologous source for fibrin glue is ideal because of the lack of risk of disease transmission by this type of product. Finally, institutional development of protocols for fibrin glue production should be encouraged, because these materials actually appear to reduce the need for blood products in some patients.34 Whereas the production of single-donor fibrin glue may meet the current need for this product in the United States at the present time, a decision clearly must be made as to whether carefully prepared commercial fibrin glue products are worth the risk. What information would be helpful in making this decision? First, it is evident that many reports on the use of commercial glue products in humans are anecdotal and often fail to use adequate control groups for comparison purposes. Animal experiments generally are better designed, but their applicability to similar human surgical procedures remains uncertain. Carefully designed studies that demonstrate a clear benefit from fibrin glue application would undoubtedly make the decision about the use of this material easier. Second, questions about viral infectivity still remain as a central concern with commercial products. Current evidence suggests that the potential for viral exposure through the use of these agents is small, and in fact, this risk may be less than that of receiving multiple additional blood products to achieve operative hemostasis. Developing technologies in the fractionation industry may make these risks even smaller. Some potential methods for lessening the risk of virus transmission include the application of solvent-detergent purification methods, modified heat treatment, or monoclonal antibody purification techniques to the manufacture of fibrin glue.12 These strategies may ultimately make this valuable product available in the United States, although such availability is undoubtedly at least several years away. Until safe commercial products become available, however,
the use of fibrin glue-preferably from autologous and single-donor sources-should be strongly encouraged by the blood banking community. References 1. Ellis DAF, Pelausa EO. Fibrin glue in facial plastic and rcconstructive surgery. J Otolaryngol 1988;17:74-7. 2. Matras H. Fibrin seal: the state of the art. J Oral Maxillofac Surg 1985;43:605-11. 3. Kram HB, Nathan RC, Mackabee JR, Klein SR, Shoemaker WC. Clinical use of nonautologous fibrin gluc. Am Surg 1988:54:570-3. 4. Drcsdale A, Rose EA, Jeevanandam V, Recmtsma K, Bowman FO, Malm JR. Preparation of fibrin gluc from single-donor freshfrozen plasma. Surgery 1985:97:750-5. 5 . Weisman RA, Torsiglicri AJ, Schreibcr AD, Epsfcin GH. Biochemical characterization of autologous fibrinogen adhesive. Laryngoscope 1987;97:1186-90. 6. Matras H, Dinges HP, Lassmann H, Mamoli B. (Suturc-frcc interfascicular ncwe transplantation in animal cxperiments] (Ger) Wicn Med Wochenschr 1972;122:517-23. 7. Bovc JR. Fibrinogcn-is thc benefit worth the risk? Transfusion 1978;19:129-36. 8. Petcrsen JK. Clinical experience in oral surgery with human fibrin sealant. Int Dent J 1985;35:277-9. 9. Schelling G, Block T, Coke1 M, Blankc E, Hammer C, Brcndcl W. Application of a fibrinogen-thrombin-collagen-based hcmostyptic agent in experimental injuries of liver and splecn. J Trauma 1988;28:472-5. 10. Durham LH, Willatt DJ, Yung MW, Jones I, Stevenson PA, Ramadan MF. A method for prcparation of fibrin gluc. J Laryngol Otoi 1987;101:1182-6. 11. Sicdentop KH, Harris DM, Ham K, Sanchez B. Extended experimental and preliminary surgical findings with autologous fibrin tissue adhesive made from patient’s own blood. Laryngoscope 1986;96: 1062-4. 12. Clark DB, Drohan WN, Miekka SI, Katz AJ. Strategy for purification of coagulation factor concentrates. Ann Clin Lab Sci 1989; 19: 196-207. 13. Cain JE, Dryer RF, Barton BR. Evaluation of dural closure techniques. Suture methods, fibrin adhesive sealant, and cyanoacrylate polymer. Spine 1988;13:720-5. 14. Hilfenhaus J, Weidmann E. Fibrin glue safety: inactivation of potential viral contaminants by pasteurization of thc human plasma componcnts. Arzneimittelforschung 1985;35:1617-9. 15. Moront MG, Katz NM, O’Connell J, Hoy GR. The use of topical fibrin gluc at cannulation sites in nconatcs. Surg Gynecol Obstct 1988;166:358-9. 16. Kennedy JG, Saundcrs RL. Usc of cryoprccipitatc coagulum 10 control tumor-bcd bleeding. Case report. J Neurosurg 1984;60:1099-
101. 17. Lupinefti FM, Stoncy WS, Alford WC, ct al. Cryoprccipitatctopical thrombin gluc. Initial expcriencc in patients undcrgoing cardiac operations. J Thorac Cardiovasc Surg 1985;90:502-5. 18. Rousou JA, Engclman RM, Breyer RH. Fibrin gluc: a n cffective hemostatic agent for nonsuturablc intraoperafivc blccding. Ann Thorac Surg 1984;38:409-10. 19. Moretz WH Jr, Shea JJ Jr, Emmett JR, Shca JJ 111. A simple autologous fibrinogen glue for ofologic surgcry. Otolaryngol Head Neck Surg 1986;95:122-4. 20. Spotnitz WD, Mintz PD, Avcry N, Bithcll TC, Kaul S , Nolan SP. Fibrin glue from stored human plasma. An inexpcnsive and efficient mcfhod for local blood bank prcparation. Am Surg 1987;53:460-2. 21. Dresdale A, Bowman FO, Malm JR, et al. Hcmostatic cffccfivcness of fibrin glue derived from singlc-donor frcsh frozcn plasma. Ann Thorac Surg 1985;40:385-7. 22. Wan HL, Huang ST, Floyd DM, McGowan EI, Feldman DS. Is the amount of fibrinogen in cryoprccipitate adequate for fibrin glue? Introducing an improved recycled cryoprccipitatc mcthod (abstract). Transfusion 1989;29(Suppl):41S.
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23. Feldman MD, Sataloff RT, Choi HY, Ballas SK. Compatibility of autologous fibrin adhesivc with implant materials. Arch Otolaryngol Head Neck Surg 1988;114:182-5. 24. Sicdentop KH, Harris DM, Sanchez B. Autologous fibrin tissue adhesive. Laryngoscope 1985;95:1074-6. 25. Silberstcin LE, Williams LT,Hughlctt MA, Magec DA, Weisman RA. An autologous fibrinogen-based advcsive for use in otologic surgery. Transfusion 1988;28:319-21. 26. 21 CFR 5 640.50. 27. Holland PV, Schmidt PJ, cds. Standards for blood banks and transfusion services. 12th ed. Arlington: American Association of Blood Banks, 1987:B4110. 28. Marshall S. Commercial fibrinogen, autogenous plasma, whole blood and cryoprecipitate for coagulum pyelolithotomy: a comparative study. J Urol 1978;119:310-1. 29. Siedcntop KH, Harris DM, Sanchez B. Autologous fibrin tissue adhesive: factors influencing bonding power. Laryngoscope 1988;98:731-3. 30. Schlag G, Rcdl H. Fibrin sealant in orthopedic surgery. Clin Orthop 1988;227:269-85. 31. Harris DM, Sicdcntop KH, Ham KR, Sanchez B. Autologous fibrin tissue adhcsivc biodcgration and systcmic effects. Laryngoscope 1987;97: 1141-4. 32. Wolner E. Fibrin gluing in cardiovascular surgery. Thorac Cardiovasc Surg 1982;30:236-7. 33. Haverich A, Walterbusch G, Borst HG. The use of fibrin glue for sealing vascular prostheses of high porosity. Thorac Cardiovasc Surg 1981;29:252-4. 34. Spotnitz WD, Dalton MS, Baker JW, Nolan SP. Reduction of perioperative hemorrhage by anterior mediastinal spray application of fibrin gluc during cardiac operations. Ann Thorac Surg 1987;44:529-31. 35. McCarthy PM, Trastek VF, Bell DG, et al. The effectiveness of fibrin glue sealant for reducing experimental pulmonary air leak. Ann Thorac Surg 1988;45:203-5. 36. Goldman CD, Blocker SH, Ternberg JL, Crouch EC. Management of experimental pncumothorax in weanling rabbits with the use of fibrin glue sclerosant. Arch Surg 1986;121:565-8. 37. Narakas A. The use of fibrin glue in repair of peripheral nerves. Orthop Clin North Am 1988;19:187-99. 38. Lucht U, Biinger C, Maller JT, Joyce F, Plcnk H Jr. Fibrin sealant in bone transplantation. No effects on blood flow and bone formation in dogs. Acta Orthop Scand 1986;57:19-24. 39. Gundry SR, Behrendt DM. A quantitative and qualitative comparison of fibrin glue, albumin, and blood as agcnts to pretrcat porous vascular grafts. J Surg Res 1987;43:75-7. 40. Borsf HG, Haverich A, Walterbusch G, Maatz W. Fibrin adhcsive: an important hemostatic adjunct in cardiovascular operations. J Thorac Cardiovasc Surg 1982;84:548-53. 41. Kram HB, Shoemakcr WC, Hino ST, Chiang HS, Harley DP, Flcming AW. Trachcal rcpair with fibrin glue. J Thorac Cardiovasc Surg 1985;90:771-5.
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42. Jessen C, Sharma P. Use of fibrin glue in thoracic surgery. Ann Thorac Surg 1985;39:521-4. 43. Scheele J, Gentsch HH, Mattcson E. Splenic repair by fibrin tissue adhcsive and collagen flcece. Surgery 1984;95:6-13. 44. Kram HB, Shoemaker WC, Hino ST, Harley DP. Splenic salvage using biologic glue. Arch Surg 1984;119:1309-11. 45. Blocker SH, Ternberg JL. Traumatic livcr laceration in the newborn: repair with fibrin gluc. J Pediatr Surg 1986;21:369-71. 46. Kram HB, Reuben BI, Fleming AW, Shoemakcr WC. Usc of fibrin glue in hepatic trauma. N Trauma 1988;28:1195-201. 47. Masur H, Fauci AS. Infections in the compromised host. In: Braunwald E, Isselbachcr KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal rncdicinc. 11th ed. New York: McGraw-Hill, 1987:469. 48. Margarit C, Martinez-lb6iez V, Lloret J, ct al. Segrncntal livcr transplantation in pigs: use of a fibrin scalant and collagen as hemostatic agents. Transplant Proc 1987; 19:3835-7. 49. Lilius P. Fibrin adhcsivc: its use in selected skin grafting. Practical note. Scdnd J Plast Reconstr Surg Hand Surg 1987;21:245-8. 50. Lindsey WH, Masterson TM, Llancras M, Spotnitz WD, Wancbo HJ, Morgan RF. Scroma prcvcntion using fibrin glue during modified radical neck disscction i n a rat modcl. A m J Surg 1988;156:310-3. 51. Jonk A, van Dongen JA, Kroon BBR. Prcvcntion of scroma following axillary lymph node dissection or radical mastectomy; ineffectiveness of fibrin glue sealing techniquc (lertcr). Neth J Surg 1987;39:135. 52. Mafras H. The use of fibrin sealant in oral and maxillofacial surgery. J Oral Maxillofac Surg 1982;40:617-22. 53. Pini Prato GP, Cortellini P, Agudio G, Clauser C. Human fibrin glue versus sutures in periodonfal surgery. J Periodontol 1987;58:426-31. 54. Baudo F, deCataldo F, Landonio G, Muti G. Managcrnent of oral bleeding in haemophilic patients (letter). Lancet 1988;2:1082. 55. Nishihira S, McCaffrey TV.The use of fibrin glue for the repair of experimental CSF rhinorrhea. Laryngoscope 1988;98:625-7. 56. Kjacrgaard J, Nordkild P, Sjmtoft E, Hjorrrup A. Non-suturcd fibrin adhesive vs. sutured anastomosis. A comparativc inrra-individual study in dog colon. Acta Chir Scand 1987;153:599-601. 57. Houston KA, Rotstein OD. Fibrin scnlant in high-risk colonic anastomoses. Arch Surg 1988;123:230-4. 58. Kram HB, Garces MA, Klein SR, Shoemaker WC. Conlmon bilc duct anastomosis using fibrin glue. Arch Surg 1985;120:1250-6.
Joan W. Gibble, MD, Associate Medical Director of Blood Scrvices, American Red Cross Blood Scrviccs, Chesapeake Region, 4700 Mount Hope Drive, Baltimore, MD 21215. [Reprint rcqucsts] Paul M. Ness, MD, Dircctor of the Blood Bank, Johns Hopkins Hospital , Baltimore, MD, and Executive Dircctor of Blood Services, Amcrican Red Cross Blood Services, Chcsapcake Region.
