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Eur J Cardiothorac Surg 2000;17:8-13
© 2000 Elsevier Science NL

Experimental study on the in vivo behaviour of a new collagen glue in lung surgery

^a Department of Thoracic and Vascular Surgery, Avicenne Hospital, F-93009 Bobigny, France
^b Department of Anatomy and Experimental Surgery, School of Medicine, University of Paris XIII, Martine Midy Foundation, Bobigny, France
^c Department of Pathologic Anatomy, Avicenne Hospital, F-93009 Bobigny, France

Corresponding author. Tel.: +33-1-4895-5231; fax: +33-1-4836-9731
e-mail: anatomie{at}smbh.univ-paris13.fr

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

 
Objective: To study the pneumostatic ability of a collagen polymerised with a polysaccharide (GAO^TM) glue in lung surgery; its influence in pleuro-pulmonary adhesion formation; the pulmonary tissue reaction to it, its biodegradability, and the eventual alterations of pulmonary compliance induced by the glue. Methods: Two groups of ten rabbits (controls and treated) were operated under ventilatory assistance by thoracotomy to promote pleural adhesions, and injury to the lung. Repeated chest X-rays were carried out postoperatively. Lungs were examined histologically at day 40. In vitro tests were performed to study glue effects on pulmonary compliance. Results: Air leaks stopped 2 min after glue application. Persistent pneumothorax were likely seen in treated rabbits (ns). Glue induces a temporary reduction of pulmonary compliance. Glue did not increase adhesion formation, or interfere with the healing process. Conclusions: For its properties, GAO seems to be a good and well-tolerated tool to reduce air leaks from the lung, without inducing residual pleural symphysis.

Key Words: Biologic glue • Thoracic surgery • Lung • Experimental study

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

 
Different adhesive products have been used in thoracic surgery in order to minimise air leaks in typical or atypical excision lung operations. The ideal product must achieve an efficient pneumostasis while reducing the adhesion formation in the pleural space, which makes the reoperations difficult.

The aims of this work are to study the pneumostatic ability of a glue consisting of a collagen polymerised with a polysaccharide (GAO–Laboratoire Perouse Implant (LPI), Lyon, France) in lung surgery; to study its influence in pleuro-pulmonary adhesion formation; to assess the pulmonary tissue reaction to this glue, as well as its biodegradability. A further objective involves the study of the eventual alterations of pulmonary compliance induced by the collagen glue.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

 
Two groups of ten female New Zealand rabbits, 3 kg in weight, namely a control group and a treated group, were included in this protocol. All animals have received care in compliance with the European Convention on Animal Care.

2.1. Biologic glue
Biologic glue is composed of macromolecular polyaldehyde and purified collagen. Purified collagen is pepsinised type I of bovine origin. Collagen is extracted from young calf's dermis, by means of a procedure, which has been validated, in order to avoid any contamination by virus and non-conventional agents. The administration kit consists of two syringes connected to a mixing device. The syringe containing the collagen is coated by a heating film connected to a 6-V battery. This kit is ready-to-use in 3 min.

2.2. Surgical procedure
The animals were fasted for 2 h before the operation. Oral antibiotic prophylaxis was started 2 h prior to the operation and continued for 7 days. There was 400 mg sulfamethoxasole plus 80 mg trimethoprim in each 500-ml bottle of drinking water.

Anaesthetic premedication consisted of atropine (0.08 mg/kg intramuscular) 15 min before the operation. Anaesthesia consisted of an intravenous administration of ketamine (25 mg/kg) plus xylazine (5 mg/kg). Further administration of 50–200 mg of ketamine was necessary during the operation.

Animals were operated under strict aseptic conditions. After shaving and disinfection of the skin, a median supra-sternal 2-cm length incision was made. Muscular layers of the neck were dissected in order to expose the cervical trachea. A transverse tracheotomy was performed and a 3.6-mm diameter paediatric cannula was introduced into the trachea. Rabbits were put under assisted ventilation (Osiris Category I ‘Transport’) at 40 cycles/min and at 3-5 l/min (FiO₂ 60%).

A left posterolateral thoracotomy was performed in order to expose the left lower lobe, as well as the lower part of the upper lobe. Abrasion of the parietal pleura was made by means of a compress hyssop, in order to promote the adhesion of the parenchyma to the chest wall. Several superficial incisions (average 7) were performed on the pulmonary parenchyma with a scalpel, inducing an air leak. A mark was made on the scalpel blade with a sterile adhesive strip, in order to assure 1.5-mm depth incisions. In the treated group, these incisions were covered with a layer of GAO glue (1 ml). The presence or absence of an air leak was verified under 4–8 mbar PEP (positive expiratory pressure) 2 min later. The operation was completed by putting a thoracic drain under water, and closing the thoracotomy by layers (Vicryl^TM 2/0 running suture) under PEP, then closing the skin with an Ethicrin^TM 2/0 running suture.

After extubation, the tracheotomy was closed with a Prolene^TM 6/0 running suture. The neck was closed by layers (muscles with Vicryl^TM 2/0, skin with Ethicrin^TM 2/0)

The thoracic drain was removed 30 min after the rabbits were awake.

2.3. Pneumostasis evaluation
Peroperatively, pneumostasis was assessed by the absence of bubbles from the lung in both groups. Postoperatively, it was assessed by a qualitative evaluation of bubbling in the thoracic drain as none, mild and severe.

Radiologically, the presence of air in the pleural cavity was evidenced by chest X-rays at days 0, 1, 4–5, 7 and more if necessary. Pneumothorax was quantified with a graphic board (Wacom^TM), measurements being performed with NIH Image 1.61 software. The ratio pneumothorax surface/total thoracic surface was calculated, and the results were analysed statistically.

2.4. Pleuro-pulmonary adhesions assessment
The animals were sacrificed 40 days following the operation (average 42 days). Necropsy was performed via a sternotomy, and the left pleural cavity was opened. After qualitative assessment of the adhesions, the left lung was excised for histological examination, in order to evaluate the inflammatory reaction, the presence of biologic glue, the foreign body reaction and the healing process.

2.5. In vitro mechanical test
In order to assess an eventual alteration of the pulmonary compliance and distensibility by the biologic glue, an in vitro test was performed.

At the moment of the necropsy, the right lung (non-operated) was removed, and its lower lobar bronchus was cannulated. After assurance that there was no air leak, the lung was insufflated with 20 cc air for 10 s (V_max). Maximal pressure (P_max) after insufflation was measured by a Hi-Lo^TM manometer (Mallinckrodt, Germany). The volume spontaneously ejected by the lung was also measured, in order to calculate the corresponding pulmonary volume (V_min) and the residual pressure into the lung (P_min). Once these measurements are made, the glue was applied on the whole surface of the lower lobe of the lung, and the test was performed again in the same manner. In this way, each lung was its self-control. Compliance was calculated as follows: C= V/ P=V_max-V_min/P_max-P_min.

Lung distensibility was estimated by the ratio between volume injected and maximal lung pressure at the end of the injection (V_max/P_max), this pressure being in inverse relation to the distensibility.

These tests were also performed on the operated lungs in order to compare the same parameters more than 40 days after the glue application.

The statistical tests used were the Spearmann and Mann–Whitney U-tests. A P-value of less than 0.05 was considered significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

 
3.1. Morbidity and mortality
Two rabbits (one in each group) died as a result of the anaesthesia.

The remaining 18 rabbits had an uneventful postoperative course. There was no respiratory distress even if a pneumothorax persisted in some cases.

3.2. Per- and postoperative pneumostasis assessment
Biologic glue stopped any macroscopic air leak from the lung incisions 2 min after its application in all cases. Pneumostasis was assessed under positive expiratory pressure. In control rabbits, an air leak was persistent at the moment of the thoracotomy closure.

Bubbling in thoracic drain was estimated qualitatively as none, mild or severe. In control group, there was no bubbling in one case, mild bubbling in four cases and severe in four other cases. Bubbles were absent in five cases in treated group, and mild in the remaining four.

3.3. Radiological monitoring
Chest X-rays were performed in all cases up to the 5th postoperative day (Fig. 1). Further radiographs were obtained if a severe pneumothorax was still present. In the control group, only two rabbits have necessitated an X-ray at day 6, then at day 15, while six rabbits in the treated groups required follow-up after the 10th day. These results are shown in Table 1. Statistics did not show a significant difference between the groups.

View larger version (176K): [in this window] [in a new window]   Fig. 1. Chest X-ray. Pneumothorax in a treated rabbit at day 4. Arrows mark the lung border.

0 (absence of adhesions): three cases in control group, two cases in treated group;

1 (one adhesion): two cases in each group;

2 (two–three adhesions): two cases in control group, three cases in treated group;

3 (more than three adhesions): two cases in each group.

In all but two cases these adhesions were loose and the lung was easy to free up from the wall by simple traction, two exceptions occurred in the control group, in which the adhesions had to be cut with scissors, because of their density.

3.5. Histological examination
Incisions on the lung were identified as a thick fibrocellular zone with capillary and lymphatic dilatation and mesothelial coverage. This healing zone was similar in the two groups. Adhesions mainly consisted of fibroblasts and collagen fibres, and presented the same characteristics in both groups.

In seven rabbits from the treated group the presence of a few giant cells-granulomas with a foreign refringent material inside has been identified. This foreign-body reaction in the scar zones and in the adhesions reflects the presence of glue debris (Fig. 2).

View larger version (137K): [in this window] [in a new window]   Fig. 2. Magnification of an adhesion showing a giant-cell granuloma containing refringent material, in a treated rabbit. Haematoxilin–eosin. x10.

3.6. In vitro lung compliance tests
Pulmonary compliance calculated as C=V_max-V_min/P_max/P_min, was significantly higher in non-operated untreated lungs than in the glued lungs (0.58 ml/cmH₂O vs. 0.40 ml/cmH₂O, respectively, P=0.04).

Distensibility estimated as V_max/P_max, was also significantly higher in untreated lungs (0.89 ml/cmH₂O vs. 0.66 ml/cmH₂O, respectively, P=0.0007).

These same tests performed more than 40 days after the operation on operated lungs, show no significant difference between control and treated groups. These results are shown in Table 2.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

In vitro tests have demonstrated that cyanoacrylate has the greater adhesive strength. However, it is not biological, and it is unabsorbable, building an impenetrable, rigid barrier, with no elasticity. Its use is not encouraged in pulmonary surgery [1]. However, it was successfully used in endoscopic closure of broncho-pleural fistulae [2].

GRFG was widely used as adhesive and hemostatic material in vascular surgery, especially in aortic dissections [3–5]. Several experimental and clinical studies in thoracic surgery [6–8] demonstrated that GRFG offers a good pneumostasis on pulmonary parenchyma. An experimental work by Ennker et al. showed that GRFG provoked serious necrotic lesions on the pulmonary parenchyma. In order to attempt to minimize this phenomenon, as well as the potential mutagenic and carcinogenic effect of the formaldehyde, these authors have replaced this compound by aliphatic dialdehydes (GR-DIAL) testing the new product in the rabbit. Despite these changes, significant fibrosis has been observed, as well as a parenchymal destruction depending on the thickness of the glue layer [1].

The adhesive most widely used in surgery is fibrin glue. Experimental trials have proved that it has a lesser adhesive power than other glues [1,6,9], even if several experimental works report its efficacy as a pneumostatic agent on small pulmonary defects [10–15]. However, the experimental study by Petsas et al. dealing with the use of fibrin glue for percutaneous biopsy of the lung, shows no significant differences between control and treated groups in overall incidence of pneumothorax, but they describe a significantly lower incidence of severe pneumothorax after treatment [15]. Another experimental study in the dog, performed by McCarthy et al. with the aim to quantify the air leaks, demonstrated that fibrin glue reduces the air leak flow during the 90 min following the operation. However, there was no significant difference between the groups concerning the persistence of pneumothorax during the first 24 h. Over this period, pneumothorax was not controlled.

Several publications report the efficacy of fibrin glue when it is systematically used to prevent or to reduce the air leaks from the operations on pulmonary parenchyma [16–22]. However, most clinical studies are not randomized and involve heterogeneous groups of patients. Wong's work is an exception, for his randomized trial on lung resections and decortications in 66 patients, shows no difference between the groups concerning times of thoracic drainage and hospitalization. According to this author, fibrin glue does not present any particular advantages, as far as costs and risks of viral transmission are considered [18]. Fleischer et al. reach the same conclusions in their randomized study on lobectomies in 28 patients [21].

Few experimental works deal with the formation of pleuro-parietal adhesions [13,14]. McCarthy et al. [14] did not find a significant difference between control and fibrin glue groups concerning adhesion formation.

Fibrin glue preparations from multiple donors raise the problem of a virtual viral transmission [18,23]. Furthermore, cases of anaphylactic reaction and severe hypotension with fibrin glue have been described [24–26]. Several teams have developed autologous preparation techniques to obtain fibrin glue from a single donor in order to reduce the risk of viral contamination [17,19,20,27,28]. In a comparative study on the efficacy of different preparations of fibrin glue, Siriex et al. [29] demonstrated that industrially prepared fibrin glue is more efficient as a hemostatic agent than autologous ones, because it contains more fibrinogen.

GAO is a collagen glue polymerized with a polysaccharide. This glue has an instantaneous adhesive power (2 min). Its biodegradation depends on its polyaldehyde concentration; at 3% the glue disappears from an intraperitoneal application in 14 days, according to the manufacturer. The aim of our study was to check the ability of this glue to seal air leaks, as well as its influence on adhesion formation. In an animal model, where it is necessary to remove the thoracic drain earlier, the only way to assess pulmonary expansion is by performing follow-up radiographs. The efficacy of GAO glue to seal air leaks was demonstrated during the operation. The pneumothoraces in the treated group persisted longer than in controls. Even if not significant, this may be explained by the fact that GAO glue reduces pulmonary distensibility and compliance, as it was demonstrated by the in vitro tests. This ‘shell’ effect, very important in rabbits who have a small pulmonary surface, should be negligible in man. Furthermore, the effect on distensibility is temporary, as proved by the tests performed on operated lungs at the time of the necropsy.

Applying a glue to prevent air leaks results in fear adhesions between the lung and the chest wall, making difficult any further intervention. In this study, even if adhesions were promoted by thoracotomy, pleural abrasion and pulmonary injuries, adhesions formed in treated lungs were loose and pauce.

We have also studied GAO glue biocompatibility. At histologic examination, GAO glue did not interfere with the healing process in the lung injury zone. Good tolerance of this glue was evidenced by the absence of inflammatory reaction. The presence of glue debris was identified by a mild foreign-body reaction containing a refringent material, reflecting the biodegradation process at the moment of the sacrifice.

	5. Conclusion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

 
Under the present experimental setting, GAO glue seems to be a good and well-tolerated tool to reduce air leaks from the lung, without inducing a residual pleural symphysis. These results need to be confirmed by further experimental and clinical trials.

	Acknowledgments

 
The authors thank Jean-Claude Meriguet from the Department of Radiology, Avicenne Hospital, for his kind co-operation in radiological monitoring.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jacques Azorin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feito, B. A. Articles by Azorin, J. Search for Related Content PubMed PubMed Citation Articles by Feito, B. A. Articles by Azorin, J.