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J Thorac Cardiovasc Surg 1999;117:751-758
© 1999 Mosby, Inc.

GENERAL THORACIC SURGERY

EXPERIMENTAL AND CLINICAL EVALUATION OF A NEW SYNTHETIC, ABSORBABLE SEALANT TO REDUCE AIR LEAKS IN THORACIC OPERATIONS

From the Departments of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie-Lannelongue Hôpital, Paris-Sud University, Le Plessis Robinson, France^a; Thoracic Surgery, Harvard Medical School, Massachusetts General Hospital, Boston, Mass^b; and Statistics Unlimited, Inc, Westford, Mass.^c

Received for publication July 24, 1998. Revisions requested Oct 30, 1998. Revisions received Nov 23, 1998. Accepted for publication Nov 23, 1998. Address for reprints: Paolo Macchiarini, MD, PhD, Department of Thoracic and Vascular Surgery, Heidehaus Hospital (Hannover Medical School), 70, Leineufer, D-30419, Hannover, Germany.

	Abstract

Top Abstract Introduction Materials and methods Results Discussion References

 
Background: Air leaks after pulmonary resections may contribute to increased patient morbidity, delayed removal of chest drainage tubes, and prolonged hospitalization. Objective: The purpose of this study was to investigate the effects of a new synthetic, absorbable sealant on the healing of healthy bronchial and lung tissues (experimental study) and its safety and efficacy to stop air leaks after lung resection (clinical study).
Methods: Fifteen large white pigs underwent a left upper lobectomy. All parenchymal surgical sites were sealed; the bronchial stump was either stapled, sealed, or both (n = 5 each). In the clinical study, 26 consecutive patients were prospectively randomized, intraoperatively, to standard closure of parenchymal surgical sites with (n = 15) or without (n = 11) the sealant.
Results: In the experimental study, no postoperative air leaks occurred, with intact bronchial closures and normal tissues at death. In the clinical study, 100% of intraoperative leaks were sealed versus 18% of control patients (P = .001). Although 77% (n = 10) of treated patients remained leak-free from the end of the operation to chest tube removal versus 9% (n = 1) of control patients (P = .001), there was no statistical difference in the duration of postoperative chest tube time, hospital stay, or cost. There were no acute or late undesirable side-effects related to the sealant application.
Conclusions: The surgical adhesive investigated here demonstrated a compelling safety profile and significant clinical efficacy to stop air leaks after lung resections.

	Introduction

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Air leaks occur at pulmonary tissue sites that have been dissected during surgical resection and/or manipulation. Most small-flow air leaks, resulting from inaccurate or unsuccessful closure of distal bronchioles or alveolar spaces, are innocuous and of short duration. ^1,2 Persisting excessive air leaks, however, represent a major complication because they extend chest tube drainage, length of hospital stay, overall morbidity, and health care costs. ^1-5

Recently, a new synthetic, absorbable surgical sealant has proved biocompatibility and effectiveness as a dural ⁶ and lung ⁷ sealant in a canine model. On this basis, we first investigated the effects of this adhesive on healthy bronchial and lung tissues in a pig model and then conducted a prospective randomized clinical study, investigating the safety and efficacy of this adhesive to reduce parenchymal air leaks after lung resections.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion References

 
Experimental study
Fifteen large white pigs (25-40 kg) underwent a left upper lobectomy, performed by 2 of us (P.M. and J.W.). The lung fissure was always stapled, and all areas of parenchymal dissections were treated with the surgical sealant; the bronchial stump was randomly stapled (group 1), stapled and sealed (group 2), or sealed only (group 3). Each study group included 5 animals. All animals received care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" formulated by the National Academy of Sciences (NIH publication No. 85-23, revised 1985).

General anesthesia was induced with ketamine hydrochloride (20 mg/kg intramuscularly) and inhalation of isoflurane by mask as needed to enable endotracheal intubation. A surgical plane of anesthesia was maintained using isoflurane (1%-3% as needed) delivered through a semiclosed rebreathing system. Perioperative antibiotics (cefazolin, 22 mg/kg intravenously) were initiated at induction. Lactated Ringer's solution was given at 22 mg/kg/h through a marginal ear vein during the surgical procedure. The animals were positioned in right lateral decubitus position, and the thoracic cavity was entered through the fourth intercostal space. The fissure between the left upper and lower lobes was divided with a linear cutting stapler (TA 55; United States Surgical Corporation, Auto Suture Company Division, Norwalk, Conn); the vascular supply was ligated, and the left upper lobe bronchus was divided. Depending on study group, the bronchus was either stapled with a 30-mm mechanical stapler (groups 1 and 2) or incised primarily approximately 4 mm from the lobar take-off origin (group 3). Group 1 animals received no additional treatment after the stapling of the bronchial stump. Group 2 animals had approximately 2 to 3 mL of hydrogel sealant applied and polymerized over the staple closure. Group 3 animals had no suture or staple closure and had a 4 to 5 mm open bronchial stump into which 2 to 3 mL of hydrogel sealant was applied and polymerized. All bronchial closures were leak tested to 40 cm H₂O, the thoracic cavity was thoroughly lavaged, fluid was evaluated, a 16F chest tube was placed, and the wound was closed in layers. The chest tube was intermittently monitored for air and fluid output over 48 hours. Thoracic radiographs were taken on postoperative days 3 and 5. Postoperative oral cephalosporin antibiotics were continued for 7 days. Animals were killed at 6 weeks; the trachea was harvested at the origin of the left upper lobe bronchus, and porcine tissues were paraffin embedded, processed, and stained with hematoxylin and eosin.

Clinical study
This open-labeled, randomized study was conducted in accordance with the Medical Device Directive and the European Standard (EN 540) for clinical investigation of medical devices for human subjects (British Standards Institution publication, 615.471: 615.478: 620.1; 1993, pp. 62-78). The protocol was approved by the Paris-Sud University and Marie-Lannelongue Ethics Committees and operations were made by 2 of us (P.M. and P.D.). All consecutive patients scheduled for pulmonary lobectomy or lesser resection by a thoracotomy between July 1996 and January 1997 were screened for eligibility to enter the study within 2 weeks of their operation; witnessed, informed consent was obtained before the procedure. Inclusion criteria included age (18 years); platelets (100,000 cells/mm³); alanine aminotransferase, aspertate aminotransferase, and alkaline phosphatase levels (1.5 of upper limit of normal); bilirubin level (1.5 mg/dL); creatinine level (2.0 mg/dL); prothrombin time (15 seconds), and patient ability to provide informed consent. Any woman of child-bearing age required a negative pregnancy test (human chorionic gonadotropin urine or serum) within 7 days before the operation. The following patients were excluded: patients undergoing pneumonectomy, women who were pregnant or lactating, patients with a history or laboratory evidence of hemostatic abnormality or a lack of hemostasis at operation, patients not expected to be available for follow-up, patients who had undergone investigational therapy within 28 days before the operation or who were scheduled to receive such therapy within 30 days of the operation, and any patient with severe congestive heart failure, cor pulmonale, and/or renal failure.

Patients enrolled in the study underwent their scheduled thoracic procedure, during which the determination was made as to whether they remained eligible for randomization. After a lobectomy or lesser resection with standard suture and/or staple closure, all surgical sites were identified. A surgical site was defined as any site that had been manipulated and was assumed to be at risk for air leakage, including all staple lines, suture lines, areas of dissection and adhesiolysis. Next, sterile saline solution was poured into the chest cavity; the lung was submerged in the saline solution to check for the presence or absence of air bubbles, and the location of each surgical site was recorded. Each surgical site was graded with the lung submersed in saline solution and inflated to pressures of 20 to 40 cm H₂O; the presence or absence of air leaks was scored as grades 0 (no leak), 1 (countable bubbles), 2 (stream of bubbles), and 3 (coalesced bubbles). If any grade 3 leaks were identified, the investigator used suture or stapler to close the leak or at least reduce it to a lower grade; saline-solution submersion was repeated, and the final grade was recorded.

The randomization scheme was prepared by the study statistician, and the randomization for each patient was maintained in a sealed envelope. After the grading of surgical sites for leaks, the envelopes were sequentially opened, and the patient was entered into either the treatment or control group of the study. Patients assigned to the control group received standard surgical management. Patients assigned to the treatment group had the synthetic sealant applied to all identified surgical sites (including those sites graded 0, nonleaking), excluding the bronchial stump, followed by a repeat saline-solution submersion test. If any leaks persisted or if new sites were identified, additional sealant was applied as necessary. A final submersion test was performed, and a posttreatment grade for each identified site was recorded. On postoperative days 1, 3, 7 (and/or day of discharge), 30, and 60, all patients underwent a safety evaluation including an assessment of daily chest tube output. Safety evaluations included physical examinations to monitor for potential allergic or inflammatory reactions or compromised wound healing. Serum chemistries and hematologic parameters were used to assess renal and liver functions or any unanticipated toxicity. A further safety evaluation was made 18 months after the operation for those patients who were still alive and included all examinations mentioned.

Sealant material
The surgical lung sealant (Focal Inc, Lexington) is a synthetic absorbable biomaterial consisting of 2 components, a primer and the sealant. The primary component of the sealant is a difunctional macromonomer composed of polyethyleneglycol, linked to trimethylene carbonate moieties, which are in turn linked to acrylate endgroups (Fig 1, A). The primer is reconstituted at the time of operation and, when brushed onto the target tissue through the applicator, acts as a wetting solution to prepare the surface of tissue for good adhesion. The clear liquid polymer is delivered and mixed into the primer, then a bead of the polymer is applied from the applicator over the target tissue to form a thin coating that, when photopolymerized by visible light, forms a biocompatible, elastic hydrogel patch. Photopolymerization is accomplished by formulating the macromers in buffered saline solutions containing triethanolamine and eosin Y as the photoinitiator. Visible light illumination from a xenon arc lamp (470-520 nm) at an intensity of 100 mW/cm² is used to initiate polymerization for 40 seconds. The sealant is about 80% water by weight and acts as a flexible, mechanical leakage barrier for 14 days, allowing full tissue expansion and normal tissue healing at the treated site. Once implanted, the sealant material degrades by hydrolysis (Fig 1, B), releasing biocompatible components that are metabolized or cleared by the kidneys. The rates of property and mass loss are determined by the hydrolyzable linkage, and the material undergoes a characteristic and predictable breakdown pattern.

View larger version (37K): [in this window] [in a new window]   Fig. 1. The surgical sealant components (A) and life cycle (B).

All statistical comparisons were based on 2-sided P values and used an level of .05. Variables measured on a continuous scale were analyzed with the Wilcoxon rank sum test. ⁸ All categoric variables were analyzed with Fisher's exact or Pearson's <² test. ⁹ The distributions of time to last air leak sealed and time to last chest tube removal were compared with the log rank test and the generalized Wilcoxon test. ⁸The distributions of laboratory severity grades were analyzed with each patient's highest postoperation laboratory grade (day 1- discharge). Comparisons with respect to maximum postoperation grade included only patients whose baseline value was in the normal range and were carried out with the Mantel-Haenszel <² test. ¹⁰ The mean hospitalization cost per patient was calculated according to the French National Cost Study (DH/PMSI/92, No. 8 from February 28, 1992), which takes into account the direct expenses affected to the individual patient, expenses of the medical and technical procedures, hospitalization expenses registered in the different clinical units attended by the patient, and administrative and structural expenses. However, it does not include the costs of the sealant, which is distributed in Europe for the reduction of air leaks after pulmonary operation by Ethicon, Inc (Johnson & Johnson; AdvaSeal) at approximately $450 per kit; the equipment is provided free of charge.

The manufacturer (Focal, Inc) provided customary financial support only to offset the administrative costs of conducting this study.

	Results

Top Abstract Introduction Materials and methods Results Discussion References

 
Experimental study
The intraoperative characteristics were not significantly different among the 3 groups (Table I). None of the animals experienced infection, dyspnea, or discomfort during the study period. No postoperative air leaks occurred. Endoscopically, the bronchial stumps showed mucosal apposition with no evidence of fistulas in groups 1 and 2. Group 3 animals showed an intact and clear, visible sealant that was tightly adherent to the bronchial mucosa on days 3 and 5; a neomucosa had formed across its surface re-establishing mucosal continuity of the bronchial stump on day 42.

View larger version (125K): [in this window] [in a new window]   Fig. 2. The section taken just proximal to the sealant plug (arrow) shows an organized fibrovascular scar that is bridging across and filling the entire bronchial lumen (note hyaline cartilage lower right and left side of frame). The sealants present right center frame surrounded by a cuff of macrophages; note the lack of foreign body giant cell formation and viable cells in contact with it. (Hematoxylin and eosin stain; original magnification, x25.)

Lobectomy was the primary procedure for both groups (10 treatment and 3 control), followed by 1 treatment bilobectomy and 5 wedge resections (2 treatment and 3 control). Overall, there was no statistically significant difference between the treatment and control groups with respect to the number of surgical sites per patient (P = .83; Table III). After the baseline saline-solution submersion test and reduction of grade 3 leaks before the randomization, only 1 patient (8%) in the treatment group and 2 patients (18%) in the control group had no air leaks (P = .58). Table IV shows that staple-line leaks (43%) were less frequently observed than suture-line (60%) and dissection leaks (59%) (P = . 22). There was no statistically significant difference in the overall distribution of prerandomization air leak grades (P = .09; Table V).

View larger version (144K): [in this window] [in a new window]   Fig. 3. High-power field of the inflammatory reaction against the sealant 19 days after the operation. As in our preclinical experience, the sealant (*) was surrounded by a cuff of large macrophages, fibroblasts, and lymphocytes. (Hematoxylin and eosin stain; original magnification, x40.)

	Discussion

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The sealant evaluated in this study is totally synthetic and adheres well to the applied tissues. The hydrogel is polymerized in situ with 2 parts, a primer and a sealant, as a laminate, forming a highly adherent coating of any desired thickness on the tissue. A laminate structure is used to provide good bonding to tissue (primer layer) and good mechanical properties (sealant layer) for sealing the leak and maintaining the seal during lung movement. The materials are applied to tissue in aqueous solution formulations. The primer solution is first brushed onto the tissue. The brushing action allows the primer material to obtain good intimate contact with the tissue surface, replacing the surface moisture. The sealant material is then gently mixed with the primer with a brush to provide a transition layer between the primer and sealant layers. The final, thicker sealant layer is then flowed over the application area, and the laminate is photopolymerized. Preclinically, it was shown to adhere 4 times more and withstand pressures 12 times greater than could be tolerated by reference surgical sealant materials (Focal Inc; personal communication, 1998). Once polymerized, the sealant is clear, allowing good visualization of target tissue. It has a compliance matched to human lung tissue (28 vs 29.4 kPa, respectively) and the capability to expand to over 700% its own size, ensuring that neither the sealant nor the lung tissue is torn during respiration and that the lung tissue beneath the sealant is normally ventilated. Histologic evaluation of the immunogenicity of the sealant material has been shown in preclinical studies to be similar to that seen with suture materials. ¹¹

In the present experience, the synthetic sealant was totally effective in eliminating intraoperative air leaks. In the experimental study, the sealant was able to avoid postoperative leaks arising from the dissected lung tissues and the bronchial stumps. Interestingly, the stapled lung tissues were always normal. The bronchoscopic examinations showed an intact seal bridging the walls of the bronchial stump on days 3 and 5 after the operation and a respiratory neomucosa re-epithelializing the adhesive surface at death, with no evidence of cellular or microbial ingrowth. This and its safe biologic profile renders the investigated sealant particularly attractive for a potential clinical application in treating bronchopleural fistulas. However, a recent yet unpublished clinical study investigating the preventive effects of the sealant on the bronchial stump after lobectomy was associated with a high incidence of bronchopleural fistula. A plausible explanation of this evidence could be that the synthetic sealant applied to the bronchial stump acted as a mechanical barrier preventing adhesion formation and eliminating a natural source of revascularization, resulting in slower healing therefore favoring the genesis of bronchopleural fistula. However, our preliminary experience with patients with postpneumonectomy or postlobectomy bronchopleural fistulas is encouraging because the application of the sealant avoided the hazards of the postpneumonectomy bronchial stump mediastinal dissection ¹² and resulted in a long-lasting closure and no undesirable local or systemic side effects (personal communication, 1998).

In the clinical study, the sealant was easy to use and apply in all anatomic areas, did not elicit a clinically demonstrable host response, and did not result in any significant changes in laboratory parameters necessitating interventional treatment across the varied study population included in the treatment group. Intraoperatively, the material remained clear, adherent, and expandable and was able to eliminate all air leaks on normal and diseased lung tissue. After the operation, the proportion of patients who were air-leak free was significantly higher in the treatment group, suggesting that the sealant maintained its adhesive properties over time. Although there was a tendency toward a shorter chest tube time and hospitalization time and costs in treated patients, this trend did not reach statistical significance in our study. These end points are currently under clinical investigation in a large, multi-institutional trial in the United States.

In conclusion, the sealant device investigated here achieved the intended performance as a soft tissue reinforcement to be used for sealing or reducing air leaks that occur during pulmonary operation.

	Acknowledgments

 
We thank Chantal Verriest, Rémi Burel, Pascal Gusmini, and Hegésippe Langouste for technical contributions. We are especially grateful for the help, support, and patient care provided by the nurses, doctors, and laboratory staff of the Marie- Lannelongue Hospital.

	References

Top Abstract Introduction Materials and methods Results Discussion References

 

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