Gelatin-Resorcinol Formaldehyde-Glutaraldehyde Glue for Sealing Pulmonary Air Leaks During Thoracoscopic Operation

Transcription

1 Gelatin-Resorcinol Formaldehyde-Glutaraldehyde Glue for Sealing Pulmonary Air Leaks During Thoracoscopic Operation Hiroaki Nomori, MD, Hirotoshi Horio, MD, Shojiroh Morinaga, MD, and Keiichi Suemasu, MD Departments of Surgery and Pathology, Saiseikai Central Hospital, Tokyo, Japan Background. Intraoperative pulmonary air leakage is one of the most troublesome complications in video-assisted thoracoscopic surgical procedures. We developed a sealing procedure using gelatin-resorcinol formaldehydeglutaraldehyde (GRFG) glue for pulmonary air leaks during such operations. Methods. Formaldehyde-glutaraldehyde (FG) jelly is prepared by mixing FG fluid with 2.5% sodium carboxymethyl cellulose to make the FG fluid viscous. We performed an adhesion-strength test to determine the optimum ratio of gelatin-resorcinol mixture to FG jelly and then conducted an air leakage test on swine lung to compare the sealing effect between fibrin and GRFG glues. To study the histotoxicity of the GRFG glue, the sealant was applied to injured rabbit lung, and the rabbits were followed for 1 day to 188 days. For clinical studies, we developed an endosyringe to apply the GRFG glue on the target site during video-assisted thoracoscopic surgical procedures and used this technique in 21 patients with intraoperative air leaks. In addition, the side effects of GRFG glue application were studied in 52 patients in whom glue was used in several ways during lung operations. Results. The results of the adhesion-strength test favored a 2:1 gelatin-resorcinol to FG ratio. The mean pressure required to produce air leakage was significantly higher with GRFG glue than with fibrin glue (p < 0.001). No critical histologic damage was seen in the rabbit lung, and the glue persisted on the lung surface for 188 days after sealing. Clinical application of the glue in 21 patients resulted in complete stoppage of air leakage during operation and long afterward, except in 1 patient with a late-onset lung fistula. The FG jelly helped prevent glue spillage at the target site, regardless of angle. A transient rise in temperature up to 38.6 C was observed as a side effect 7 days after operation in 5 (9.6%) of the 52 patients. Conclusions. A GRFG glue using FG jelly seals pulmonary air leaks effectively, simply, and safely during video-assisted thoracoscopic surgical procedures. (Ann Thorac Surg 1999;67:212 6) 1999 by The Society of Thoracic Surgeons One of the most troublesome complications in videoassisted thoracoscopic surgery (VATS) is intraoperative or prolonged air leakage from the lung [1, 2]. Pulmonary parenchymal defects are difficult to suture during VATS, and suturing often both damages the normal lung and fails to stop the air leak. Fibrin glue applied as a sealant frequently did not halt the leak and even caused it to recur postoperatively because of the poor tissue-bonding strength of the glue [3]. Use of gelatin-resorcinol formaldehyde-glutaraldehyde (GRFG) glue as a tissue adhesive and hemostatic agent was reported in 1966 [4, 5], and since 1979, has been successfully applied during operations for aortic dissection [6 8]. Taking advantage of these features, we [9] developed a lung excision procedure using a GRFG glue spreading stapler to prevent air leakage from the staple line. We have now tested a procedure to seal pulmonary air leaks during VATS by applying GRFG glue with a dedicated instrument. Here we report the procedures, the experimental results, and the Accepted for publication June 19, Address reprint requests to Dr Nomori, Department of Surgery, Saiseikai Central Hospital, Mita, Minato-ku, Tokyo , Japan. clinical results. We also discuss the side effects of GRFG glue as seen in 52 patients who underwent operation on the lung. Material and Methods Laboratory Experiments The GRFG glue is manufactured by Cardial SA (Saint Étienne, France). To give viscosity to the formaldehydeglutaraldehyde (FG) fluid, it is mixed with 2.5% sodium carboxymethyl cellulose (Koso Chemical Co, Ltd, Tokyo, Japan) to produce a fluid gel [9]. We performed an adhesion-strength test using bovine pericardial strips (Bio-Vascular, Inc, Saint Paul, MN) to determine the optimum ratio of gelatin-resorcinol (GR) mixture to FG jelly [9]. Two bovine pericardial strips 4 cm long and 1 cm wide were used (Fig 1). The GR mixture and the FG jelly were studied at ratios of 8:1, 4:1, 2:1, 1:1, 1:2, and 1:3. The ratios constituted 0.2 ml of GR mixture and FG jelly volumes ranging from to 0.6 ml. The combinations to be tested were spread on an edge of each of two strips measuring 1 1 cm, and each strip was 1999 by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)

2 Ann Thorac Surg NOMORI ET AL 1999;67:212 6 GRFG GLUE SEALING 213 Fig 1. Adhesion-strength test. Two bovine pericardial strips that were overlapped at the edges after the application of gelatin-resorcinol formaldehyde-glutaraldehyde glue were pulled away from each other using a spring scale. (Modified from [9] by permission of The Society of Thoracic Surgeons.) attached firmly to the other with a compression weight of 1.0 kg. Ten minutes later, the edges of the strips were pulled horizontally using a spring scale (IM-20DX; Intesco Co, Matsudo, Japan), and the weight at which the strips pulled apart was measured. A control was prepared from 0.2 ml of GR mixture and 0.02 ml of the original FG fluid. The experiment was repeated three times for each ratio. We conducted an air leakage test using swine lung to compare the sealing effect of fibrin glue and GRFG glue. Two swine, 1 weighing 30 kg and the other, 35 kg, were anesthetized, intubated using a Broncho-Cath tracheal tube (Mallinckrodt Med., Athlone, Ireland) for one-lung ventilation, and ventilated with a respirator (Fancy 80 Monitor Animal; Kimura Med., Tokyo, Japan). After a right thoracotomy, a peripheral strip 2 mm deep, 15 mm long, and 10 mm wide was cut from the lateral surface of the lung. The lung was immersed in normal saline solution, and air leakage was quantified by maintaining pressure at which leakage first occurred for 30 seconds. Fibrin glue (Beriplast-P; Behringwerke AG, Frankfurt, Germany), 0.1 ml, was applied through a double syringe to cover the lung wound, as specified by the manufacturer. The GRFG glue was placed directly on the lung wound with a syringe by applying 0.7 ml of GR, and then 0.35 ml of FG jelly and mixing them to completely cover the wound. Glued surfaces were kept at rest using one-lung ventilation for 5 minutes. The lung was again ventilated after immersion in normal saline solution, and pressure was monitored. The experiment was repeated three times on different wounds for both fibrin glue and GRFG glue in each swine. Eleven adult Japanese White rabbits, 3 months old and weighing 2.6 to 3.0 kg, were used to study GRFG glue histotoxicity. The rabbits were premedicated with a subcutaneous injection of ketamine hydrochloride (10 mg/kg) and xylazine hydrochloride (2.5 mg/kg). Ventilation during the operation was conducted through a tracheostomy using a pressure-controlled respirator (Fancy 80 Monitor Animal) and 0.5% halothane inhalation. The maximum airway pressure was kept at 13 cm H 2 O, and the respiratory rate was 25/min. After a left thoracotomy, a peripheral strip 2 mm deep and 10 mm in diameter was cut from the lateral surface of the left lower lobe. The GRFG glue was placed on the lung wound as a GR mixture of 0.7 ml followed immediately by 0.35 ml of FG jelly, which was mixed with the GR to cover the wound completely. Three minutes after gluing, air leakage and bleeding stopped, and the chest incision was closed without a chest tube. Animals were disconnected from the ventilator after recovery of normal breathing. Chloromycetin (chloramphenicol) (60 mg) was administered intramuscularly from 1 day to 4 days after operation. Rabbits were sacrificed 1 day, 2 days, 3, 5, 7, 10, 14, 21, 28, 56, and 188 days after operation. All animals received humane care as specified in the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 85-23, revised 1985). Clinical Studies We developed an endosyringe to mix the GR and FG components easily and to place the glue on the target for clinical use during VATS. The endosyringe is 35 cm long and has an outside diameter of 1.0 cm. The tip is circular and has six holes, suitable for applying sufficient glue on the target site and for combining the two components. The GR mixture was packed into the endosyringe and conducted to the target site through a trocar with the patient under one-lung ventilation (Fig 2). Immediately thereafter, the FG jelly was applied from another endosyringe and mixed with the GR using the same endosyringe. To seal air leaks on the vertical or bottom lung surface, the target site was turned upward by forceps and then sealed with glue. A seal was confirmed after 2 minutes by a pressure loading of 20 cm H 2 O, and the thoracic cavity was washed to remove excessive FG jelly. Fig 2. The gelatin-resorcinol mixture was placed on the target site, immediately followed by formaldehyde-glutaraldehyde jelly sealing, using an endosyringe through a trocar during one-lung ventilation. (GRFG gelatin-resorcinol formaldehyde-glutaraldehyde.)

3 214 NOMORI ET AL Ann Thorac Surg GRFG GLUE SEALING 1999;67:212 6 Fig 3. Adhesion-strength test results showed no significant difference in strength between control (original glue of formaldehyde-glutaraldehyde [FG] fluid) and glue with FG jelly at gelatin-resorcinol to FG ratios of 2:1 and 1:1. We used this technique from October 1996 to October 1997 to seal pulmonary air leaks in 21 patients who were quantified for air leaks under pressures of less than 10 cm H 2 O. The mean GR mixture volume required in these patients was ml. The side effects of GRFG glue were investigated using physical, laboratory, and chest roentgenographic findings in 52 patients who underwent a lung operation between May 1996 and October Of these 52 patients, 24 were treated with a GRFG glue spreading stapler to prevent air leak [9], 7 received GRFG glue to seal pulmonary air leaks under open thoracotomy, and 21 underwent the procedure described here. Results Laboratory Experiments The adhesion-strength test showed the control glue (GR mixture and original FG fluid) adhesion to be 1, g (Fig 3). The FG jelly strength was gataGRtoFG ratio of 8:1, g at a 4:1 ratio, g at 2:1, g at 1:1, g at 1:2, and g at 1:3. Adhesiveness at ratios of 8:1, 4:1, 1:2, and 1:3 were significantly lower than for the control ( p 0.001), but no difference was observed for ratios of 2:1 and 1:1. To minimize the use of cytotoxic FG, we selected the GR to FG ratio of 2:1 for the experiments and clinical use. The mean pressure required to produce air leak in untreated swine lung wounds (controls) was cm H 2 O (Fig 4). Air leakage from wounds after GRFG glue treatment was produced at a mean pressure of cm H 2 O, significantly higher than cm H 2 O after fibrin glue treatment ( p 0.001). The GRFG glue promptly stopped both air leakage and bleeding in the experiment with injured rabbit lung. Histologic studies demonstrated the lung surface with Fig 4. Air leakage test results showed that gelatin-resorcinol formaldehyde-glutaraldehyde (GRFG) glue has significantly more pressure tolerance than fibrin glue (p 0.001). the glue, the necrotic area, the inflammatory zone, and then normal lung, in this order, and the findings were monitored from 1 day to 188 days after sealing (Fig 5). Glue persisted on the lung surface for 188 days after sealing and then became encased in granulation tissue and glue-filled macrophages. Glue was decreased by macrophage phagocytosis from 56 days after sealing, but approximately 80% of it remained at 188 days. The necrotic zone was 2 mm wide 1 day after sealing but gradually decreased and became organized from day 56. Histologic study of the inflammatory zone revealed six major findings. Polymorphonuclear leukocyte infiltration was seen mainly from 1 day to 3 days after sealing; Fig 5. Histologic findings in rabbit lung 5 days after glue sealing. (Hematoxylin and eosin; 7.5 before 33% reduction.) (G glue; I inflammatory zone; N necrotic zone.)

4 Ann Thorac Surg NOMORI ET AL 1999;67:212 6 GRFG GLUE SEALING 215 Clinical Studies The GRFG glue completely sealed pulmonary air leaks during VATS in all patients (Fig 6). There were no air leaks or instances of pneumothorax even late postoperatively except in 1 patient with a late-onset lung fistula. The FG jelly helped prevent spillage at the target site, regardless of the angle, because of its viscosity. The endosyringe is suitable for sealing and mixing GRFG glue at the target site during VATS. All chest tubes were removed within 4 days after operation (mean time, 2.8 days postoperatively). Five (9.6%) of the 52 patients experienced side effects after operation involving GRFG glue. Two of the patients were treated with the procedure described here, 2 were treated with the glue-spreading stapler, and 1 had glue treatment under open thoracotomy. These patients had satisfactory postoperative courses with no fever from 3 days after operation, but at 7 days, they suddenly had a rise in temperature to 38.1 to 38.6 C that lasted for 3 days. Although the precise causal relationship with use of GRFG glue was unclear, these patients had no signs of infection on chest roentgenograms and cultures of sputum, urine, and blood. Temperatures returned to normal after medication with an antiinflammatory drug and antibiotics for 3 days, and the patients were discharged from the hospital 9 or 12 days after operation with no further problems. The other patients showed no fever from 4 days after operation. One patient had development of a lung fistula 6 days after GRFG glue sealing at the wedge resection staple line. This 69-year-old man had single-lung metastasis in the right lower lobe from a thyroid carcinoma associated with non-insulin-dependent diabetes mellitus. In the first operation, the stapler had to cut deeply toward the lung hilum to excise the tumor, and GRFG glue was used to seal air leakage at the staple line, thus allowing the chest tube to be removed 2 days after operation. Reoperation revealed tissue necrosis at a lung fistula where GRFG glue had been applied. Suturing the lung fistula under open thoracotomy stopped the air leak, and the patient was discharged from the hospital 20 days after reoperation. No other side effects were observed in any patient during the mean follow-up of 32 weeks. Fig 6. Nearly white gelatin-resorcinol formaldehyde-glutaraldehyde glue (arrow) seals pulmonary air leakage sufficiently during videoassisted thoracoscopic surgical procedure. lymphocyte infiltration appeared after 5 days and increased until 28 days after sealing; macrophage infiltration was most apparent from 10 to 21 days after sealing; foreign-body giant cells appeared from 5 to 56 days after sealing and were most conspicuous at 14 days; organization and fibrosis appeared after 10 days, gradually increased until 56 days after sealing, and then decreased until 188 days; and minor calcification appeared 56 and 188 days after sealing. Comment Gelatin-resorcinol formaldehyde-glutaraldehyde glue has been used in hemostasis and as an adhesive agent in reconstructive vascular surgery [6 8]. In Japan, use of GRFG glue is approved for use for hemostasis of the lung and the liver. An investigation using rabbit lung also indicated the usefulness of GRFG glue in sealing pulmonary air leaks [10]. In VATS, however, GRFG glue is difficult to apply accurately at the target site because the liquid FG fluid easily spills from the target site and because no adequate glue-sealing instruments for the lung have yet been commercialized. Spillage of FG fluid is particularly critical because the material is highly histotoxic. We used FG jelly to make the FG fluid viscous and to help prevent spillage at the target site, regardless of the angle. The adhesion-strength test showed no significant decrease in adhesiveness between the original FG fluid and the FG jelly at a GR to FG ratio of 2:1, the ratio used in the experiments and clinical studies. The discrepancy in optimum ratios between the original FG fluid (control) (10:1) and the FG jelly (2:1) may be due to jelly mixing. Fibrin glue has been shown in experiments to effectively seal pulmonary air leaks [11 13]. Türk and associates [11] reported that fibrin glue sealing of the suture line significantly increased pressure tolerance compared with conventional lung sutures when tested intraoperatively. Thoracic surgeons, however, have often found that for pulmonary parenchymal defects, fibrin gluing without suturing fails to prevent air leaks during operation and tends to cause recurring postoperative leaks. In a randomized study, Fleisher and coworkers [3] found that routine use of fibrin glue does not effectively reduce the duration of air leakage, chest tube drainage, or hospitalization after lobectomy. In contrast, in studies using injured rabbit lungs, Bellotto and colleagues [10] noted that GRFG glue effectively sealed pulmonary air leaks. The results of our air leakage test in swine lung showed that GRFG glue has much greater pressure tolerance than fibrin glue. From 1966 to 1969, the glue consisted of a GR mixture and 37% formaldehyde (GRF glue), and its histologic effects were examined in animal studies [5, 14]. Currently, a combination of 16.5% formaldehyde and 10% glutaraldehyde (FG fluid) is used instead of 37% formaldehyde because of the lower toxicity and better polymer-

5 216 NOMORI ET AL Ann Thorac Surg GRFG GLUE SEALING 1999;67:212 6 ization with the GR mixture. In previous experiments [5, 15], formaldehyde was applied first directly to the injured lung, followed immediately by the GR mixture. To prevent direct damage to the lung by the FG component, we reversed the sequence in both the experiments and the clinical work, ie, the GR mixture was placed on the injured lung first and was followed immediately by application of the FG jelly. Histologic studies of rabbit lung showed a necrotic zone beneath the glue, a finding seen in previous experiments and possibly the result of the FG component. No further critical histologic damage was seen, however. Although the glue was decreased by macrophage phagocytosis from 56 days after sealing, most of it remained at 188 days. The long-term influence of the glue on the lung should be examined further. Suturing pleural or pulmonary parenchymal defects during VATS is technically difficult and often fails to stop air leaks. Suturing also damages normal lung tissue and compromises postoperative lung function. The results of our clinical application of GRFG glue to pulmonary air leaks during VATS are encouraging for four major reasons: All patients undergoing our procedure for pulmonary air leakage showed successful sealing during operation; postoperative air leak recurred in only 1 patient; GRFG glue was easily applied at the target site using the endosyringe; and viscous FG jelly spillage at the target site was negligible regardless of the angle. Side effects after use of GRFG glue in vascular surgical procedures have not been reported [6 8]. In our clinical experience with VATS, however, a transient fever of 3 days duration can occur 7 days postoperatively. Although the causal relationship is not clear, fever in our patients could have been due to the GRFG glue, as no signs of infection were seen. Postoperative fever could be caused by a foreign-body reaction to the gelatin because the gelatin component in the glue originates from pig skin. The late-onset lung fistula showed tissue necrosis at the GRFG glue sealed staple line. Deep cutting during stapling and diabetes mellitus could conceivably have caused this late fistula, but tissue necrosis was also possibly due to the FG component in the GRFG glue, as indicated in the histologic findings of this study. It should be noted that although GRFG glue can seal a lung fistula in most instances without causing a problem, sealing can also result in tissue necrosis beneath the glue. Objectively evaluating the efficacy of GRFG glue in sealing lung fistulas would require a randomized study involving GRFG glue sealed and fibrin glue sealed or nontreated groups. Although we have no experience with nontreatment of intraoperative air leakage during VATS, we have seen postoperative air leakage of more than 3 days duration in 7 (64%) of 11 patients who had fibrin glue applied for intraoperative air leakage during VATS. On the basis of this study and our previous experience, we conclude that GRFG glue effectively, simply, and safely seals pulmonary air leaks during VATS. References 1. McKenna RJ, Brenner M, Gelb AF, et al. A randomized prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg 1996;111: Keenan RJ, Landreneau RJ, Sciurba FC, et al. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 1996;111: Fleisher AG, Evans KG, Nelems B, Finley RJ. Effect of routine fibrin glue use on the duration of air leaks after lobectomy. Ann Thorac Surg 1990;49: Tatooles CJ, Braunwald NS. 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