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Interact CardioVasc Thorac Surg 2007;6:12-15. doi:10.1510/icvts.2006.139436 © 2007 European Association of Cardio-Thoracic Surgery
The short-term efficacy of fibrin glue combined with absorptive sheet material in visceral pleural defect repair
a Division of General Thoracic Surgery, Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan Received 3 July 2006; received in revised form 6 October 2006; accepted 9 October 2006
*Corresponding author. Tel.: +81 3 5363 3806; fax: +81 3 5363 3499.
Tissue sealants can prevent the occurrence of pulmonary air leakage, although few studies have evaluated the seal-breaking pressure properties of the various methods. We developed a new method for repairing visceral pleural defects which combines fibrin glue with a sheet material. We used an animal model to compare its efficacy with that of three current techniques up to 24 h after application. Under thoracotomy, 5x20 mm visceral pleural defects with a depth of 3 mm were made in beagles. The defects in the normal lungs were repaired using 1 of 4 methods: Method A, fibrin-glue double layer (fibrinogen solution was dripped, followed by thrombin solution); Method B, pack method (fibrin glue combined with polyglycolic acid sheet); Method C, rubbing and spray (fibrinogen was rubbed, followed by spraying of both fibrinogen and thrombin solutions); Method D, fibrin-glue-coated collagen fleece. The defects were repaired also in an emphysematous lung model using Method A, B or C. In the normal lungs, Method B showed significantly higher pressure resistance compared with the other methods at 5 min, 1 and 3 h post-application. Pressure resistance increased with time for all methods. In the emphysematous lungs, Method B showed significantly higher seal-breaking pressure than Methods A and C. Compared with existing tissue sealant methods, the pack method reliably controlled pulmonary air leakage immediately after application.
Key Words: Pulmonary air leakage; Visceral pleural defects; Tissue sealants; Emphysema; Fibrin glue
Pulmonary air leakage is a common postoperative complication of respiratory surgery, and prolonged leakages can lead to longer hospitalization, and occasionally even thoracic infections [1]. The incidence of leakage increases particularly in procedures on the emphysematous lung. Depending on the location of the defect, and the degree of underlying emphysematous change if any, suturing or stapling can be extremely difficult. Furthermore, sutures may impede reinflation of the remaining lung. It is also technically difficult to suture pulmonary air leakages in the emphysematous lung during thoracoscopy. The clinical benefits of tissue sealants in preventing pulmonary air leakages have been reported [2–8], but few studies have accurately assessed each method in terms of pressure resistance at the time of the repair and subsequent changes over time. We have previously reported differences in pressure resistance with different methods of fibrin glue application to repair pleural defects 5x10 mm in size with a depth of 2 mm. We found that the rubbing and spray method showed the highest sealing effect [9]. However, this method was not as effective when we increased the defect size to 5x20 mm with a depth of 3 mm. With these findings in mind, we developed a new method which combines the rubbing and spray method with an absorptive sheet to cover the pleural defect. In this study, we investigated the usefulness of this method up to 24 h after application. We also obtained preliminary data in the emphysematous lung.
2.1. Animals Female beagles, aged 5–7 months, weighing 8–10 kg (Toyota Trading Co., Kumamoto, Japan) were used. The sealants were fibrin glue (Bolheal®, The Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan) and fibrin-glue-coated collagen fleece (TachoComb®, ZLB Behring Co., USA). The absorptive sheet was a non-woven sheet (Neoveil®, Gunze Ltd, Kyoto, Japan), 0.15 mm in thickness. The sheet is loose, and highly elastic. 2.3. Production of pleural defects in normal canine lung Animals (n=65) were intubated under general anaesthesia (0.25 mg atropine sulfate s.c., 30 mg/kg pentabarbitol sodium i.v., 10 mg suxamethonium chloride i.v.) and placed on controlled ventilation. Right thoracotomy was done. With airway pressure maintained at 10 cmH2O, a pleural defect 5x20 mm in size with a depth of 3 mm was made on the surface of each of the anterior, middle and posterior lobes using a scalpel. The 5x20 mm defect size was determined by placement of a thin flexible metal film of this size on the visceral pleura. Bleeding was cauterised if needed, but sites where haemostasis was difficult to achieve were not used.2.4. Pleural defect repair methods The pleural defects were repaired using one of four methods. Three pleural defects were made per animal. Out of the four repair methods compared in this study, three different methods were randomly chosen to repair the three defects in one animal. Method A, fibrin-glue double layer; 0.4 ml of liquid fibrinogen is dripped onto the defect, followed by 0.4 ml of liquid thrombin. Method B, pack method; 0.2 ml of liquid fibrinogen is rubbed in gently, then a PGA sheet is placed over the defect, and 0.2 ml of liquid thrombin is sprayed onto the sheet, followed by 0.2 ml of liquid fibrinogen and 0.2 ml liquid thrombin sprayed together. The PGA sheet is cut to approximately 7x22 mm, allowing for an overlap of approximately 2 mm around the defect. Method C, rubbing and spray method; 0.2 ml of liquid fibrinogen is rubbed in gently, followed by 0.2 ml liquid fibrinogen and 0.2 ml liquid thrombin sprayed together. Method D, fibrin-glue-coated collagen fleece; cut to the same size as the PGA sheet, placed on the defect, and pressure applied for 5 min using dry gauze. Except for 5 min measurements, the chest was closed, and the animals were allowed to survive. Ketoprofen (100 mg) was administered for analgesia, and ampicillin sodium (150 mg) as prophylaxis against infection, both intramusclularly.2.5. Measurement of seal-breaking pressure in the normal lung The pressure resistance of the repaired site was measured at 1, 3, 6 and 24 h post-application under thoracotomy (Table 1). Seal-breaking pressure, the minimum positive airway pressure that produced air leakage, was measured separately for each of the three repairs, while the bronchi of the other two lobes were clamped. The highest airway pressure applied was 60 cmH2O, because air leaks could occur from the pulmonary hilum at pressures above 60 cmH2O. Following measurements at each time point, animals were killed by intracardiac injection of 1000 mg pentobarbital sodium.
2.6. Histopathological examination Separate animals (n=16) were used for the preparation of tissue specimens from normal lungs, because tissue sealants could become separated from the lung surface when seal-breaking pressures were measured. The right lungs were removed at each time point post-application (methods A, 12 sites, B, 12 sites, C, 12 sites, D, 12 sites). The lungs were fixed in 10% formalin, and the region containing each repaired pleural defect was resected, embedded in paraffin and sliced into 3-µm sections and stained with haematoxylin-eosin. 2.7. Measurement of seal-breaking pressure in the emphysematous lung Animals with the same specifications as for the normal lung experiments were anaesthetised and laid on their right side. Under bronchoscopy, a solution of 40 mg elastase (elastase type I, porcine pancreas-derived, Sigma Co., St Louis, MO, USA) diluted in 20 ml of saline, was sprayed into each segment of the right lung [10]. Animals were allowed to recover after this treatment.Six weeks after this treatment, the emphysema model animals were anaesthetised for seal-breaking pressure measurements as in the normal lung. On thoracotomy, the right lung was hyperinflated, the visceral pleura was rugged, and small airspaces were visible through the pleura. In some animals, these changes were not homogeneous, but experiments were performed in locations where these changes were evident. Pleural defects were repaired randomly as in the normal lung using Method A, B or C. Seal-breaking pressure was measured at 5 min post-application. Separate animals could not be prepared to acquire tissue specimens only, because of the time required to produce the animal emphysema model. Therefore, following seal-breaking pressure measurements, the right lung was removed, fixed in 10% formalin, and the region containing each repaired pleural defect was resected and embedded in paraffin, sliced into 3-µm sections, and stained with haematoxylin-eosin. All data are expressed as mean±standard deviation. Statistical analyses were performed using the unpaired t-test (StatView, SAS Institute Inc., Cary, NC, USA), with P<0.05 considered a significant difference.All animal studies were approved by the School of Medicine, Keio University Institutional Animal Care and Use Committee. All animals received humane care in accordance with the Japanese Government Animal Protection and Management Law.
3.1. Seal-breaking pressure in the normal lung At 5 min, 1 h and 3 h post-application, Method B showed significantly higher seal-breaking pressure than the other methods. No significant differences were seen between methods at 6 and 24 h (Fig. 1). On direct observation under thoracotomy, each tested material was securely attached to the visceral pleura. Adhesion between the parietal pleura was not apparent.
3.2. Histopathological findings in repaired normal lungs On histology, there was adequate attachment of the tissue sealant to the underlying lung surface with each repair method. There were no apparent traces of excess bleeding or inflammation in the adjacent lung, or pleura (Fig. 2).
3.3. Seal-breaking pressure in the emphysematous lung On direct observation, each tested material was securely attached to the visceral pleura. At 5 min post-application in the emphysematous lungs, Method B showed significantly higher seal-breaking pressure than Method A or C (Method A vs. B vs. C; 25±7 (n=11) vs. 37±12* (n=12) vs. 25±7 (n=7) cmH2O, *P<0.05). Seal-breaking pressure was lower in the emphysematous lung than in the normal lung for all repair methods (normal vs. emphysematous, cmH2O, Method A: 34±15 vs. 25±7, P=0.1; Method B: 55±10 vs. 37±12, P=0.01; Method C: 34±6 vs. 25±7, P=0.02), and a significant difference was seen in Methods B and C. In a separate preliminary experiment, no significant difference was seen between normal and emphysematous lungs in the seal-breaking pressure at 5 min without repair (18±3 vs. 16±7 cmH2O, P=0.4). 3.4. Histopathological findings in the emphysematous lung Histological examination revealed emphysematous changes in the lung parenchyma, particularly in the proximity of the pleura. As seal-breaking pressures had already been measured in this group, partial separation of the tissue sealant had occurred, although overall, sufficient attachment of the tissue sealant to the underlying lung surface was seen with each repair method. There were no apparent traces of excess bleeding or inflammation in the adjacent lung, or pleura (Fig. 3).
Currently available fibrin glue products are derived from plasma, in most cases human, and hence carry similar risks as blood transfusion. Despite these potential drawbacks, the benefits of fibrin glue and fibrin-glue-coated collagen fleece in preventing recurrence of pulmonary air leakages has been reported [2–8,11,12]. However, none has included an experimental evaluation of pressure resistance and efficacy of each method. Our pack method used a 0.15-mm-thick PGA sheet, which was soft and flexible because of the rough weave, and therefore presumably, fitted well into the irregular contour of the defects. Thrombin easily penetrates the sheet, but fibrinogen does not. By applying the PGA sheet over the fibrinogen, the solution is retained by the sheet fibres allowing for secure fibrin formation between the defect and the sheet following thrombin application. When solutions A and B are then sprayed together, there is an even layer of fibrin covering the defect, both under and over the sheet [13]. In the clinical setting of postoperative management, high airway pressures can occur with coughing at recovery from anaesthesia and at extubation, possibly causing rupture of the repair site and air leakage. Once a repaired pleural defect ruptures, it takes time to heal by endogenous fibrin and regeneration of the pleural membrane. The present study along with our previous study, have shown that pressure resistance increases with time, regardless of the repair method, and so it is of particular importance that there is high pressure resistance immediately post-application. In our study the only method to fulfil this expectation was the pack method (Fig. 1). Direct observation showed that with the pack method, the sealants remained adherent to the defect, as well as to the adjacent pleura, with the lung either underinflated or hyperinflated. The fibrin-glue-coated collagen fleece separated from the lung at pressures exceeding 40 cmH2O, causing air leakage. With the fibrin-glue double layer, the efficacy was inconsistent. The rubbing and spray method showed high pressure resistance with small pleural defects, but with larger defects we were unable to demonstrate significant superiority. We have not investigated whether this difference was due primarily to the increase in defect size or depth. To this end, further studies are necessary to determine the defect size or depth the pack method is able to withstand. Histological examination of the normal lung post-application showed adequate coverage of the lung surface for all repair methods. No findings that might reflect differences in pressure resistance between application methods were found. This is thought to be because the pressure resistance of tissue sealants derives from their adhesive strength in relation to physical factors such as the elasticity of the pleural membrane and the airway pressure acting on the repair site, making it difficult to assess through histological examination. Although adverse findings were not apparent in any of the methods tested up to 24 h, long-term studies are needed to further assess efficacy, and safety. On emphysematous lungs, control of air leakage becomes even more difficult. Suturing or stapling may cause new pleural defects in these cases. Furthermore, sutures may impede reinflation of the remaining lung, further reducing postoperative lung capacity in patients already suffering from impaired pulmonary function. We compared seal-breaking pressures at 5 min post-application, at which time point significantly higher seal-breaking pressure was achieved with the pack method than with the other methods. Fibrin-glue-coated collagen fleece was not evaluated due to lack of animal number, but we assume that it would not stay adherent to the hyperinflated emphysematous lung due to its stiffness. Seal-breaking pressures were lower with all methods in the emphysematous lung than in the normal lung. Little additional information regarding differences in pressure resistance between methods in the emphysematous lung was gained through histological examination. Further long-term studies are needed in this area.
We thank Drs Noriko Shinya, and Takanori Uchida at The Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan, for their experiment assistance, and fibrin glue preparation. We also thank Dr Mitsuo Nakayama for his support.
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Abstract
1. Introduction
]; Method B (pack method): fibrin glue + PGA sheet [
]; Method C: rubbing + spray 
; Method D: fibrin-glue-coated collagen fleece 
.
