Fibrin Sealant

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Abstract
Fibrin sealant (fibrin adhesive; fibrin glue; Beriplast® P1) is a haemostatic and wound support product consisting of the blood coagulation factors fibrinogen, factor XIII and thrombin, the antifibrinolytic agent aprotinin and calcium chloride. Fibrin sealant has been used to good effect in a wide variety of surgical and endoscopic procedures. Suture support was provided in series of patients with oesophageal, gastric, colonic or rectal anastomoses, and fibrin sealant was as effective in haemostasis as microcrystalline collagen powder in hepatic surgery. It did not reduce postoperative peritoneal drainage after elective cholecystectomy, however. A 41% reduction (p < 0.02) in incidence of air leakage was achieved when fibrin sealant was added to sutures in patients undergoing pulmonary resection in a randomised single-blind study. A high rate of complete remission of malignant pleural effusion has been reported after intrapleural instillation of fibrin sealant, and successful sealing of CSF leaks after trauma or surgery has also been achieved. Attenuation of prolonged or excessive haemorrhage after dental extraction has been achieved in patients on anticoagulant therapy or with haemorrhagic disorders who received fibrin sealant with packing and suturing. Repeated endoscopic injection of fibrin sealant was superior to single injection sclerotherapy with polidocanol 1% in a randomised study in 805 patients with bleeding peptic ulcers. Other data suggest that endoscopic injection of fibrin sealant is associated with lower recurrence of bleeding and need for emergency surgery than thrombin with adrenaline (epinephrine) or hypertonic saline with adrenaline. Similar haemostatic efficacy to laser photocoagulation or sclerotherapy was reported in a retrospective comparison. A statistically significant reduction relative to suturing in the incidence of wound dehiscence was reported after the use of fibrin sealant in cataract surgery, and benefit of the sealant has also been noted in patients receiving skin grafts and in those undergoing transurethral resection of the prostate gland. Conclusions: Although comparative studies would assist in the clarification of the place of the product discussed with respect to other haemostatic or wound support techniques and to other fibrin sealants, the formulation reviewed here has been shown overall to be effective and well tolerated in a variety of haemostatic and wound healing support roles in numerous types of surgery. Fibrin sealant has also been shown to be useful when administered endoscopically, with superiority over sclerotherapy being shown after repeated application in patients with peptic ulceration. Fibrin sealant can therefore be considered useful in a number of surgical and endoscopic settings. When mixed, the separate components of fibrin sealant (fibrinogen, factor XIII, thrombin, calcium chloride and aprotinin) give rise to the formation of a stable, crosslinked fibrin clot. Cell-rich granulation tissue is seen after 3 days, with proliferation of collagen fibres after 4 to 7 days. After 14 days, collagen-rich granulation tissue with markedly decreased numbers of infiltrating cells is ob-served. In vitro studies have shown that the clotting time of fibrin sealant is dependent on the concentration of thrombin in the sealant after mixing. Data from a study in rats showed inhibition of fibrinolysis to be improved by the addition of up to 1500 kallikrein inhibitory units (KIU) per ml of aprotinin per clot. Animal and in vitro data show that factor XIII is needed at a concentration of 40 to 80 U/ml to ensure adequate fibrin crosslinking, tensile strength of clots, haemostasis and adhesion. The use of fibrin sealant in addition to sutures has been shown to increase resistance to bursting of ileal anastomoses in rats, and in rabbits the preparation was most effective when applied after closure of a scierai wound. Studies with radiolabelled fibrin sealant in rats have shown that clots placed subcutaneously or intraperitoneally are progressively covered by connective tissue, decrease in weight exponentially and are no longer present after 30 days. Half-lives of subcutaneously and intraperitoneally placed clots were 4.6 and 4 days, respectively. Of doses of radiolabelled fibrin sealant applied to thigh muscle or to stomach smooth muscle, 90 and 64%, respectively, remained at the application site after 6 hours; remaining radioactivity was reduced to 1.2 and 3.5% after 7 days. Low levels of radioactivity were detected in the spleen, liver, kidney, untreated skeletal muscle and blood. Abdominal Surgery. Suture dehiscence was detected after approximately 2 weeks in 2 patients only of a series of 45 in whom fibrin sealant was applied after stapling of colonic or rectal anastomoses. ‘Minor’ or ‘major’ suture failure was reported in 7 anastomoses (5 colonic) 2 weeks after fibrin sealant was applied at a dose of 0.1 ml/cm2 to oesophageal, gastric, colonic or rectal closure sites in another 37 patients; 81.1% of these patients showed no leakage. Satisfactory haemostasis with no abscess formation was achieved in a series of 8 patients in whom fibrin sealant was sprayed onto cut liver surfaces after hepatectomy for hepatic cancer with cirrhosis. Post-biopsy bleeding was also prevented by injection of fibrin sealant into or near biopsy sites in 37 of 38 instances in 33 patients who had undergone laparoscopic liver biopsies. Fibrin sealant was as effective as microcrystalline collagen powder in the control of postoperative bleeding and bile leakage in a randomised study in 62 patients undergoing hepatic resection. However, application of fibrin sealant to the gallbladder bed after elective cholecystectomy had no effect on postoperative peritoneal drainage in a randomised comparison with no local treatment in 80 patients. The sandwich method (in which the pancreatic remnant is held closed with sutures after spraying with fibrin sealant) was superior to the sealing method (in which the sealant is sprayed over the closed pancreatic stump and sutures) in a nonrandomised comparison in 111 patients undergoing distal pancreatectomy. Thoracic and Vascular Procedures. In a single-blind study in which 59 patients were randomised to suturing alone and 55 to suturing plus fibrin sealant after pulmonary surgery, a reduction in the incidence of bronchopleural or pulmonary air leakage of 41% (p < 0.02 vs suturing alone) was associated with the use of fibrin sealant in the subpopulation of 63 patients undergoing pulmonary resection. Airway tolerance pressure testing showed improvement after application of fibrin sealant in 17(81%) of 21 patients with air bubbles after conventional suturing (1-sidedp value Neurosurgery and Ear, Nose and Throat Surgery. Fibrin sealant was effective in the sealing of cerebrospinal fluid (CSF) leakages after trauma or surgery in 3 case series in a total of 243 patients. Successful and permanent sealing was noted in all 57 patients who underwent repair of CSF leakage with pedunculated periosteal flaps plus fibrin sealant, whereas leakage was reported in 42.3% of 26 who underwent repair with lyophilised dura and cyanoacrylate adhesive. CSF leakage persisted in only 2 of 15 patients with intraoperative leakage during repair with septal bone and fibrin sealant of the sellar floor and anterior wall of the sphenoid sinus after transsphenoidal surgery. There was no recurrence over a minimum of 12 months in any of 104 patients in whom intraoperative leakage was not noted. Fibrin sealant was also used to good effect in a further series of 26 patients undergoing neurosurgical procedures including sealing of CSF leaks, reinforcement of aneurysmal clippings, local haemostasis and protection of cerebral veins. Oral Surgery. Fibrin sealant has been used successfully in patients undergoing oral surgery. Prolonged or excessive haemorrhage was noted in 15% of 80 patients with haemorrhagic disorders but in none of 40 patients on anticoagulant therapy who underwent dental extraction followed by packing of the extraction site with fibrin sealant and collagen fleece or gel dressing with subsequent suturing and application of further sealant. Poor initial results in patients with severe haemophilia prompted an increase in the aprotinin content of the sealant from 1000 to 10 000 KIU/ml and the addition of tranexamic acid mouthwash therapy in subsequent patients in this group. This resulted in a reduction in the incidence of bleeding from 75% to 12%. ‘Good’ results were reported in 73 of another 78 patients undergoing oral or maxillofacial surgery after use of fibrin sealant for haemostasis, packing and wound protection. Endoscopy for Peptic Ulceration. Fibrin sealant has shown efficacy in several trials and case series in patients with bleeding from peptic ulcers. Bleeding was arrested by a single endoscopic injection of fibrin sealant in 716 of a series of 955 patients, of whom 59 had presented with spurting and 156 with oozing bleeding. A randomised comparison of endoscopic sclerotherapy (single injection of polidocanol 1%) with single or multiple applications of fibrin sealant (at least 2 clots per ulcer) in 805 patients with bleeding peptic ulcers showed statistically significant reductions with repeated fibrin sealant treatment relative to polidocanol of 33.3 and 40.8%, respectively, in the rates of recurrence of bleeding and treatment failure. A statistically nonsignificant but marked decrease in risk of rebleeding was reported with repeated fibrin sealant therapy (15 vs 42% with polidocanol) in patients with spurting bleeding, with low 30-day mortality rates (4.3 to 5.3%) in all treatment groups. Endoscopic injection of fibrin sealant reduced the rate of recurrence of bleeding and need for emergency surgery by 51 and 75%, and by 43 and 100%, respectively, relative to treatment with combinations of thrombin with adrenaline (epinephrine) [after preliminary emergency treatment of all participating patients with thrombin and adrenaline] or hypertonic saline with adrenaline. Definitive haemostasis was achieved in 97% of 30 patients who received fibrin sealant in a retrospective comparison with laser photocoagulation or sclerotherapy, in which rates of haemostasis were 97 and 96%, respectively. Other Procedures. Compared with sutures, fibrin sealant reduced wound dehiscence at day 7 postoperatively (32.6 vs 11.8%; p = 0.012) and foreign body sensation in a study in 100 patients undergoing cataract removal and lens implantation in a randomised study. Good adhesion and high rates of success have been reported in series of cases in which fibrin sealant has been used to affix skin grafts. A success rate of 95 to 100% was reported in a series of 27 patients receiving skin grafts fixed into position with fibrin sealant. ‘Satisfactory’ or ‘very satisfactory’ adhesion of skin grafts was reported on the day of surgery in 75.9%ofa further series of 70 patients in whom fibrin sealant was used. ‘Almost complete take’ or better was reported by day 3 in 86.2% of cases. Median blood loss over 3 days after transurethral resection of the prostate gland was significantly reduced (30 vs 189ml; p < 0.01 vs control) by the postoperative instillation of fibrin sealant into the prostatic cavities of 15 patients in a randomised comparison in a total of 30 individuals. Overall, fibrin sealant has been associated with good tolerability in the various applications in which it has been assessed. Adverse event rates in a large randomised study comparing fibrin sealant with sclerotherapy with polidocanol 1% in patients with upper gastrointestinal bleeding were 23.8% with polidocanol, 21.4% with single injections of fibrin sealant and 24.3% with repeated fibrin sealant treatments, and were largely unrelated to therapy. In patients undergoing pulmonary surgery, adverse events were not linked to the presence or absence of fibrin sealant, and all deaths in the 3-month follow-up period were associated with underlying disease. Five-year postmarketing surveillance data from over 1 million fibrin sealant applications show 2 reports (one of severe bronchospasm and hypoxia in a child and one of anaphylactic shock in a patient also receiving antibiotic therapy) of adverse events considered to be possibly related to the use of fibrin sealant. Of 3 further Japanese reports of anaphylaxis, one has been linked to the bovine aprotinin component of the sealant. Fibrin sealant contains ingredients derived from pooled human plasma, and process controls and purification procedures are therefore in place to address concerns relating to the danger of transmission of blood-borne infectious diseases. No cases of viral infection have been definitively linked to the use of fibrin sealant. Care should be taken to avoid accidental intravascular injection of fibrin sealant (which may result in thromboembolic complications or synergism between calcium ions in the sealant and cardiac glycosides in patients taking these drugs) and to avoid unintentional contact with tissues outside the intended application site (which may cause adhesions). Fibrin sealant is available in 4 vials, as follows Vial 1. Human plasma protein fractions containing 65 to 115mg fibrinogen and 40 to 80U of factor XIII activity. Vial 2. Bovine aprotinin solution 1000 KIU/ml. Vial 3. Human plasma protein fraction containing 400 to 600IU of thrombin activity. Vial 4. Calcium chloride solution 14.7mg in 2.5ml (40 mmol/L). After reconstitution in 2 parts (fibrinogen and factor XIII with aprotinin, and thrombin with calcium chloride), sequential application (or simultaneous application via a double syringe) is suitable for small sites, whereas the solutions may be sprayed together or sequentially over larger areas. Fibrin sealant may be applied alone or in conjunction with collagen fleece, sponge or absorbable or non-absorbable mesh. The safety or otherwise of fibrin sealant in pregnant or breastfeeding women has not been evaluated.