Fibrin adhesive: An important hemostatic adjunct in cardiovascular operations

J THoRAc CARDlOVASC SURG 84:548-553, 1982

Fibrin adhesive: An important hemostatic adjunct in cardiovascular operations Fibrin adhesive was applied 413 times in a group of 340 patients undergoing extracorporeal circulation whenever conventional suturing appeared impossible. difficult, or dangerous, with a success rate of 95%. Fibrin-presealed woven or knitted fabric was inserted in 60 heparinized patients, 45 of whom underwent cardiac procedures. There was perfect sealing of the fabric in all but one instance. Fibrin gluing has become a routine method, reducing man-hours and blood loss and occasionally salvaging patients' lives. Fibrin-pre sealed knitted prostheses are expected to replace woven fabric because of its known poor healing qualities.

Hans Georg Borst, M.D. (by invitation), Axel Haverich, M.D. (by invitation), Gerd Walterbusch, M.D. (by invitation), and Winfried Maatz (by invitation), Hannover, Federal Republic of Germany Sponsored by Bruno Messmer, M.D., Aachen, Federal Republic of Germany

T

issue gluing appears to be an interesting alternative to conventional suturing. Synthetic glues have been advocated for control of bleeding':" and pulmonary air leaks" and for reapproximation of aortic dissection. 5, 6 Fibrin glue differs from synthetic glues because it mimics a biological process, i.e., the end stage of spontaneous coagulation. Importantly, fibrin adhesive is effective in the presence of systemic anticoagulation and/ or coagulopathies and does not require perfectly dry surfaces. Fibrin glue was first introduced into cardiovascular surgery by Spangler? in 1976. Akrami and co-workers" first employed the adhesive for sealing vascular grafts, This presentation describes our experience with the adhesive as a hemostatic agent and discusses its exciting potential in presealing vascular prosthetic fabric. Material and methods The adhesive consists of commercially available concentrated frozen cryoprecipitated or lyophilized From the Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Hannover Medical School, Hannover, Federal Republic of Germany. Read at the Sixty-second Annual Meeting of The American Association for Thoracic Surgery, Phoenix, Ariz., May 3-5, 1982. Address for reprints: H. G. Borst, M.D., Klinik fiir Thorax-, Herz-, und Gefaj3chirurgie, Zentrum Chirurgie, Medizinischen Hochschule Hannover, Konstanty-Gutschow-Str. 8.0-3000 Hannover 61, Federal Republic of Germany.

548

fibrinogen (Tissucol*) of human origin, which is prepared for use by either warming or dilution, respectively. The proteinaceous material is activated by an optimal mixture of bovine thrombin (500 NIH units/ ml), calcium chloride (40 mmole/L), and the antifibrinolytic agent aprotinin (3,000 kallikrein-inhibitor units/ml) (Fig. 1). The components form a firm fibrin clot after contact. For hemostatic purposes, a small amount of fibrinogen is applied to a piece of collagen fleece or sponge (Collatampt); the activator is dripped onto the material, which is then pressed on the bleeding site for approximately 60 seconds. Alternatively, the components may be applied to large oozing surfaces with the aid of a pressure-driven double-syringe spray gun* (Fig, 2). To seal pores in prostheses, the fibrinogen is smeared onto the outer surface of the stretched fabric and subsequently the activating solution is massaged into the graft. Presealed woven Cooley grafts,:j: double-velour knitted grafts (Microvelr), and simple knitted grafts (Microknit§) have been inserted in patients. An average of 1. 2 ml (0.5 to 4,0 ml) of fibrinogen was utilized for hemostatic gluing, and 2.8 ml (1.0 to 6.0 ml) was required for presealing prosthetic fabric. *Immuno AG, Vienna, Austria. tPlantorgan, Bad Zwischenahn, Federal Republic of Germany. :j:Meadox Medicals, Inc., Oakland, N. J. §Golaski Laboratories, Inc., Philadelphia, Pa. 0022-5223/82/100548+06$00.60/0

© 1982 The

C. V. Mosby Co.

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Fig. 1. Components of the fibrin glue: The vial on the right contain s thrombin and the one on the left, calcium chloride and aprotinin . The contents of the vials are mixed . Fibrinogen, drawn up in a syringe , is warmed and then applied to a suitable collagen carr ier to which the activating mixture subsequently is added (see text).

Results Although first employed to achieve hemostasis under conditions in which suturing was deemed impossible , difficult, or dangerous, the adhesive subsequently was also used to expedite the operations . Arterial bleeding could be controlled in over 95% of 243 applications. Fibrin gluing was especially useful for stopping poorly accessible hemorrhage from aortic and coronary suture lines (Table I). In 104 applications for bleeding from low-pressure sources , the fibrin adhesive failed in two instances only (Table I). It appeared particularly helpful for sealing atrial suture lines as well as puncture holes in right ventricular patches and conduits. Furthermore, the adhesive was effective in every case of diffuse reoperative epimyocardial bleeding and for smoothly attaching coronary grafts to the epicardium. In addition to the aforementioned indications, fibrin adhesive also was used for presealing prosthetic fabric . No failure occurred in 38 patients receiving woven grafts during extracorporeal circulation (Table II). Twenty-two presealed knitted grafts thus far have been implanted in the high- and the low-pressure limbs of the circulation of heparinized patients (Table II). Seven of these patients were on extracorporeal bypass as well. In the latter group there was one case of prosthetic leakage occurring a few minutes after re-establishment of spontaneous circulation . Perfect sealing of an ascending aortic prosthesis and of a right ventricle- to- pulmonary artery conduit is demonstrated in Figs. 3 and 4. Fig. 5 shows a fibrin-presealed double-velour graft recovered from a patient who died 4 months after operation of a

Fig. 2. Double-syringe pressure-dri ven spra y gun . One syringe contains fibrinogen and the other, the acti vating mixture .

descending thoracic aneurysm. Formation of a thin inner capsule and satisfactory progression of connective tissue ingrowth into the prosthesis are evident. Discussion

Although most bleeding in cardiova scular operations can be controlled by conventional means, such attempts are often associated with undue prolongation of the operation , continuing hemorrhage, and circulatory depression , all of which may jeopardize the patient's life . Hemostatic gluing , therefore, has been an interesting alternative to suturing ever since the introduction of synthetic tissue glues . J -4 However, such adhesives have been of little value in cardiovascular operations because of their dependency on absolutely dry surfaces. In contrast to synthetic adhesives, fibrin glue uses a biological system by mimicking the end stage of plasmatic coagulation, can be used in the presence of moisture, and does not produce toxicity or excessive tissue reaction ." The tensile strength of the fibrin clot does not

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Fig. 3. Fibrin-presealed knitted double-velour graft inserted in the ascending aortic position in a patient with syphilitic aneurysm.

Table I. Results of hemostatic fibr in gluing No . of applications High-pressure system Aorta CA BG distal CABG proximal LV Totals

Low-pressure system Atrial suture lines Coronary venous RV/PA conduit R V patch (PTFE) Totals

Table II. Results of fibrin presealing of grafts Failures

No .

I

%

132 59 48 4

8 2 I

6.1 3.4 2. 1

243

II

4.5

66 14 12 12 104

2

16.6

2

1.8

Others Epimyocardial bleeding Fixation of CABG Totals

45 21 66

20

0

Legend : CABG, Coronary artery bypass graft. LV, Left ventricle, R V, Right ventricle . PA, Pulmonary artery. PTFE, Polytetrafluoroethylene.

equal that of synthetic adhesives, but the finn fibrin network produced will arrest any but brisk arterial bleeding . The optimal concentrations of the components of the glue have been studied in detail , as has the addition of inhib itor substances to combat any local fibrinol ytic activity. 9 More than 1,500 applications of the adhesive have

I

___________ Woven grafts (ECC) Aortic arch Ascending aorta RV-PA co nduit Knitted grafts (heparin) Descending aorta Knitted grafts (ECC) Ascending aorta RV-PA conduit RV patch LV patch

No . of

I-NO-' -o f-

patients

failures

3 33 2 15 2 2 2

1*

I

Legend: ECG, Extracorporeal circulation . RV, Right ventricle. PA, Pulmonary artery. LV. Left ventricle. ' Delayed leakage occurred in the only nonvelour graft.

been reported in a recent workshop on fibrin gluing conducted at our institution . to Fibrin gluing was found part icularly helpful in sealing bleed ing sites difficult or impossible to approach , in locations dangerous to suture , and in arresting diffuse hemorrhage from epimyocardial wound s. Likewise , prolonged oozing from bleeding sources imperfectly controlled by suturing alone appears an ideal target for the adhesive . Fibrin glue also has been applied in prophylactic sealing of suture lines (especially in acute aortic dissection ) and of puncture holes in polytetraftuoroethylene patche s. Finally, aorta-coronary bypass grafts may be glued to the cardiac surface along any desired course by simply dis-

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Fig. 4. Fibrin-presealed knitted double-velour conduit inserted in a patient with pulmonary atresia and ventricular septal defect.

Fig. 5. Presealed knitted double-velour graft recovered 4 months after replacement of descending aorta (trichromic stain , original magnification x 500) .

tributing drops of fibrinogen along the vein and then adding a small amount of activator solution. Aside from these more practical indications , fibrin gluing was examined as a method for sealing the pores of prosthetic fabric prior to implantation . In vitro it was possible to seal various commercially available prostheses to zero water permeability . Also large-pore grafts, when implanted during extracorporeal circulation in short-term and medium-term animal experiments, remained blood-tight in every instance. I 1 As a result, we have given up natural preclotting of prosthetic fabric

for any indication involving systemic heparinization and are now exploring presealed knitted grafts rather than woven fabric even in patients requiring heart-lung bypass. Sufficient evidence including our own now is available to show that woven grafts can be sealed reliably with fibrin adhesive . A reliable seal has not always been achieved by natural preclotting, by treatment with plasma constituents ;" or by baking blood into the graft .:" Fibrin presealing, therefore, is now the preferred method for sealing woven prostheses in a number of European centers and also has greatly lowered

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blood loss in complex cardiovascular procedures involving insertion of prosthetic material."?' 14-16 Fibrin sealing of knitted grafts obviously opens exciting perspectives. It is hoped that knitted fabric ultimately will replace woven fabric with its known poor healing qualities, which recently have become so obvious in conduit operations. 17, 18 In our experience all fibrin-presealed woven grafts inserted in patients on extracorporeal bypass remained leak-proof, as did knitted velour prostheses implanted in heparinized patients. There was one failure in 22 presealed knitted grafts implanted in patients on extracorporeal circulation. Since this leakage involved the only nonvelour prosthesis utilized, we are now studying the optimal mode of applying the adhesive, the type of prostheses most suitable for sealing, and the potential role of generalized fibrinolysis as well as its possible control by systemic administration of inhibitor agents. Finally, local or systemic reactions to the adhesive when used in cardiovascular operations have not been noted. Although hepatitis virus may be transferred by fibrinogen preparations, a recent prospective study has failed to support this possibility. 19 REFERENCES I Braunwald NS, Gay W, Tatooles CJ: Evaluation of crosslinked gelatin as a tissue adhesive and hemostatic agent. An experimental study. Surgery 59: 1024-1030, 1966 2 Matsumoto T, Pani KC, Heisterkamp CA, Hamit HF: Comparative study of cyanoacrylate and cross-linked gelatin compound in hemostasis of anticoagulated wound. Milit Med 134:98-103, 1969 3 Collins JA, James PM, Levitsky SA, Bredenburg CE, Anderson RW, Leonard F, Hardaway RM: Cyanoacrylate adhesives as topical hemostatic aids. II. Clinical use in seven combat casualties. Surgery 65:260-263, 1969 4 Matsumoto T, Hardaway RM, Pani KC, Leonard F, Jennings PB, Heisterkamp CA: Cyanoacrylate tissue adhesives in the treatment of recurrent spontaneous pneumothorax. Surgery 61:573-575, 1967 5 Guilmet 0, Bachet J, Goudot B, Laurian C. Gigou F, Bical 0, Barbagelatta M: Use of biological glue in acute aortic dissection. A new surgical technique: Preliminary clinical results. J THORAC CARDIOVASC SURG 77:516521, 1979 6 Bachet J, Gigou F, Laurian C. Bical 0, Goudot B, Guilmet 0: Four-year clinical experience with the gelatinresorcine-forrnol biological glue in acute aortic dissection. J THoRAc CARDIOVASC SURG 83:212-217, 1982 7 Spangler HP: Gewebeklebung und 10kale Blutstillung mit Fibrinogen, Thrombin und Blutgerinnungsfaktor XIII. Wien Klin Wochenschr 88:Suppl 49: 1-18, 1976 8 Akrami R, Kalmar P, Pokar H, Tilsner V: Abdichtung von Kunststoffprothesen beim Ersatz der Aorta im

thorakalen Bereich. Thoraxchirurgie 26: 144-147, 1978 9 Redl H, Schlag G, Dinges H-R, Kudema H, Seelich T: Background and methods of "fibrin sealing," Biomaterials, GO Winter, OF Gibbons, H Plenk, eds., Chichester, 1982, John Wiley & Sons Ltd, pp 669-676 10 Borst HG, Haverich A, eds.: Fibrin seal in cardiovascular surgery. Proceedings of a workshop. Thorac Cardiovasc Surg 30: 195-224, 1982 II Haverich A, Walterbusch G, Borst HG: The use of fibrin glue for sealing vascular prostheses of high porosity. Thorac Cardiovasc Surg 29:252-254, 1981 12 Cooley DA, Romagnoli A, Milam JD, Bossart MI: A method of preparing woven Dacron aortic grafts to prevent interstitial hemorrhage. Cardiovascular Diseases. Bull Texas Heart Inst 8:48-52, 1981 13 Bethea MC, Reemtsma K: Graft hemostasis. An alternative to preclotting. Ann Thorac Surg 27:374, 1979 14 Koveker G, de Vivie ER, Hellberg KD: Clinical experience with fibrin glue in cardiac surgery. Thorac Cardiovasc Surg 29:287-289, 1981 15 Struck E, Laas J, Meisner H, Schmidt-Habelmann P, Sebening F: Surgical treatment of aneurysm of the thoracic aorta, Cardiovascular Surgery, W Bircks, J Ostermeyer, HD Schulte, eds., Berlin-Heidelberg-New York, 1978, Springer- Verlag, pp 439-444 16 Huth C, Seybold-Epting W, Hoffmeister H-E: Local hemostasis with fibrin glue (Tissucol") after intracardiac repair of tetralogy of Fallot and transposition of the great arteries (TGA). Thorac Cardiovasc Surg 30:Suppl 1:30, 1982 17 Agarwal KC, Edwards WD, Feldt RH, Danielson GK, Puga FJ, McGoon DC: Clinicopathological correlates of obstructed right-sided porcine-valved extracardiac conduits. J THORAC CARDIOVASC SURG 81:591-601, 1981 18 Ben-Schachar G, Nicoloff OM, Edwards JE: Separation of neointima from Dacron graft causing obstruction. J. THoRAc CARDIOVASC SURG 82:268-271, 1981 19 Scheele J, Schricker KT, Goy RD, Lampe I, Panis R: Hepatitisrisiko der Fibrinklebung in der Allgerneinchirurgie. Med Welt 32:783-788, 1981

Discussion DR. ERNST WOLNER Vienna. Austria

I have had the opportunity to use this adhesive during the past 8 years, because this fibrin glue was developed by a group in Vienna and tested for the first time experimentally and clinically for cardiovascular surgery in our institution. I can confirm the presented data from my own experience with more than 600 patients. We were able to achieve excellent results, achieving hemostasis in all cases with prostheses, outflow tract patches. conduits, and in epicardial lesions that sometimes occurred during cardiac reoperation. In the control of bleeding from vascular anastomoses, however, we have not been as successful as the authors. Our success rate in this case was only 70%, especially in spurting hemorrhage. The fibrin adhesive is a helpful adjunct in chest as well as

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cardiovascular operations. We have used it for control of superficial air leaks and bleeding after lobectomies in lung operations and to assure airtight tracheal anastomoses. In some cases we have applied this fibrin glue for the successful closure of a bronchial stump or fistula and, endoscopically, for an esophageal fistula. In conclusion, the fibrin adhesive does not replace an exact and precise surgical technique, but sometimes it can be very helpful. DR. B 0 R S T (Closing) Dr. Wolner, thank you very much for your kind comments. You are indeed a "historical figure" in fibrin gluing, because this method actually was first employed in cardiovas-

cular operations by your group in Vienna. Subsequently, it was advocated by the group of Dr. Rodewald. I think one can argue about success rates, because this is a method that may be overdone quite easily when used uncritically, i.e., in brisk arterial bleeding. The more experience the surgeon has, the more careful he is to pick patients with oozing that cannot be controlled by conventional means. This is the type of bleeding that can be easily stopped by gluing. I think the fibrin adhesive can be highly applicable to pulmonary operations. Spontaneous pneumothorax or operative laceration of the lung can be managed reliably with this glue. Gluing has become very popular in Europe and I hope will be used in the United States in the near future.