Laser Tissue Welding in Lung and Tracheobronchial Repair

Transcription

1 CHEST Laser Tissue Welding in Lung and Tracheobronchial Repair An Animal Model Original Research INTERVENTIONAL PULMONOLOGY Benjamin S. Bleier, MD ; Neri M. Cohen, MD, PhD, FCCP ; Jason D. Bloom, MD ; James N. Palmer, MD ; and Noam A. Cohen, MD, PhD Background: Violation of the integrity of the airway (pulmonary parenchymal air leak or tracheobronchial injury) remains a challenging problem in chest medicine and thoracic surgery. Tissue sealants such as fibrin glue have been suggested to improve outcomes but they are still associated with significant failure rates. Laser tissue welding (LTW) is an alternative method that produces wound repairs that are significantly stronger than those of fibrin glue and may be used to repair air leaks. Methods: We used an Institutional Animal Care and Use Committees-approved New Zealand white rabbit model of lung parenchymal and tracheal injury. Lung wounds (n 5 8 per condition) were created and either left open or repaired using fibrin glue or LTW. Tracheal wounds (n 5 5 per condition) were created using incisions in the membranous and cartilaginous portions or by removing a tracheal ring, and were repaired using LTW. Within each tissue type, the burst strength of the wounds was measured using a digital manometer and were compared with one another using a two-tailed, paired Student t test. Results: Among the lung injuries, the burst strength of the LTW repair ( mm Hg) was significantly stronger than that of the fibrin glue repair or open wound ( mm Hg, P 5.001, and mm Hg, P,.001, respectively). Among the tracheal injuries, the burst strength of the membranous incision ( mm Hg) was significantly higher than that of the cartilaginous incision ( mm Hg, P 5.03) but not that of the cartilaginous defect ( mm Hg). Conclusions: LTW is capable of sealing wounds in the tracheobronchial tree and can produce bonds that are twice as strong as fibrin glue in lung parenchyma. LTW may be a better alternative than fibrin glue in the repair of injuries to the airway. CHEST 2010; 138(2): Abbreviations: LTW 5 laser tissue welding Pulmonary air leaks following thoracic surgery are a common complication in patients. These leaks seal spontaneously in the majority of cases; however, there remains a population of patients who require Manuscript received November 15, 2009; revision accepted February 17, Affiliations: From the Division of Rhinology, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina (Dr Bleier), Charleston, SC; the Department of Thoracic Surgery, Greater Baltimore Medical Center (Dr N. M. Cohen), Baltimore, MD; and the Department of Otorhinolaryngology-Head and Neck Surgery (Drs Bloom, Palmer, and N. A. Cohen), University of Pennsylvania, Philadelphia, PA. Correspondence to: Benjamin S. Bleier, MD, Division of Rhinology, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, 135 Rutledge Ave, MSC 550, Charleston, SC 29425; bleierb@gmail.com further intervention. The use of biologic sealants such as fibrin glue in a variety of endoscopic and open approaches in an effort to repair the lung parenchyma and prevent recurrence has been described. These techniques still carry a significant failure rate that may be due, in part, to the intrinsic limitations of the adhesive strength of fibrin glue. Laser tissue welding (LTW) is a technique that uses laser energy to polymerize an albumin-based tissue solder. LTW is capable of producing repairs that are significantly stronger. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( site/misc/reprints.xhtml ). DOI: /chest CHEST / 138 / 2 / AUGUST,

2 than those of traditional fibrin glues and may be used to reduce recurrence rates in this difficult patient population.1 Management of persistent violation of the integrity of the airway (parenchymal air leaks or tracheobronchial injury) remains a significant challenge. Patients who develop this condition as a result of disease (bullous emphysema, spontaneous pneumothorax, bronchopleural fistula from advanced-stage malignancy), trauma, or therapeutic interventions (persistent air leak after pulmonary surgery, postlobectomy or pneumonectomy airway stump closure failure, tracheobronchial injury from airway instrumentation) suffer increased morbidity and mortality. 2-4 Traditional tissue apposition techniques, such as suturing and stapling, are often ineffective in creating an airtight seal, given the intrinsic friability of the lung parenchyma. 3 As a result, a significant effort has been directed toward developing techniques that use tissue glues to seal the air leak through a variety of minimally invasive approaches. 3,4 Fibrin glue is a widely available and commonly used tissue sealant in this application; however, its efficacy may be limited by its poor intrinsic burst strength. 5 LTW represents an alternative technique that may be used to improve the success of these repairs. It uses an albumin-based solder doped with a gelling agent and a laser-specific chromophore that fuses tissue edges through protein denaturation. The addition of the chromophore enables the solder to absorb the vast majority of the laser energy, thereby enabling albumin denaturation in a spatially precise manner with much lower collateral thermal spread than would be seen with electrocautery. These welds have been shown to produce tissue bonds capable of withstanding pressures up to four times those of fibrin glue and can therefore be used to repair tissue injured as a result of surgical misadventure or difficult tissue planes (reoperative conditions), or after trauma. Novel gelling agents have been introduced recently that have further improved the performance of LTW in a variety of applications. The purpose of this study was to (1) examine the performance of LTW in three distinct types of airway tissue, (2) compare this performance to fibrin glue in lung parenchymal tissue, and (3) compare the strength and lasing times of two different solder gelling agents. wavelength output, nm. The preparation of the biologic solder was based on previously described techniques. 6 It was composed of a 1:2 mixture of bovine serum albumin (Fisher Scientific; Pittsburgh, PA) and indocyanine green dye (Sigma-Aldrich; St Louis, MO). Based on the solder formulation used, either hyaluronic acid (Sigma-Aldrich) or chitosan (Ultrasan; Laval, QC, Canada) was used as a gelling agent. In the fibrin glue studies, a commercially available formulation (Tisseel; Baxter; Deerfield, IL) was used in accordance with its package insert. Burst Threshold Manometry The manometry system is composed of a closed air-filled system with a traceable manometer (range, to mm Hg [Fisher Scientific]) and a 60-mL syringe arranged in parallel with a pediatric 2.5-mm cuffed endotracheal tube ( Fig 1 ). In all studies, the endotracheal tube is introduced into the proximal trachea and an airtight seal is created by the application of a circumferential 2-0 silk suture proximal to the inflated cuff. The syringe is used to inject air into the system, and the pneumatic pressure of the system is recorded on the digital manometer. The burst threshold is determined by the maximal pressure at which an air leak occurs at the wound site. Sample Size The formula below is used to calculate the sample size for the respective comparisons in this study. This formula is used considering a error with z a as specified. N 5 ([z a ] s 2 ) / d 2 where z a 5 value for a error (1.96); s 2 5 variance (9); d 5 difference to be detected (4); and N 5 number of subjects per study group. A minimum of five wounds are studied per condition because our sample size calculation demonstrated a need for at least four subjects for each condition to provide adequate power. Materials and Methods Laser System and Solder Preparation A diode laser module (Iridex; Mountain View, CA) was used, coupled to a 600- m m-core-diameter quartz silica fiberoptic cable with the following specifications: power, 1.0 W; pulse duration, 0.5 s; pulse interval, 0.1 s; power density, 31.8 W/cm 2 ; major Figure 1. Burst threshold manometry system demonstrating a digital manometer (M) attached in parallel with a 60-mL air-filled syringe (S) and a 2.5-mm cuffed endotracheal tube (E). 346 Original Research

3 Experimental Groups This study used tissue derived from 16 3 to 5-kg New Zealand white rabbits that were killed under a separate protocol and whose use was approved by our Institutional Animal Care and Use Committee (approval ). In the lung parenchymal injury arm, three conditions were studied using eight data points per condition. These included unrepaired injury, fibrin glue repair, and laser-welded repair using the chitosan-based solder. In all cases, the physiologic baseline burst threshold of the lung tissue was determined prior to injury by measuring the pressure required to inflate the lung to its maximal intrathoracic volume. In the tracheal injury arm, two separate studies were carried out. In the first study, the chitosan-based solder was used to study three conditions using five data points per condition. These included repair of a 5-mm membranous and cartilaginous incision, as well as a mm cartilaginous defect. In all cases, the burst threshold of the unrepaired tracheal injury was determined prior to repair. The second study compared the burst thresholds of a 5-mm cartilaginous incision repair between the chitosan- and hyaluronic acid-based solders. In this study, total welding time was recorded as the lasing time required to achieve an adequate weld following solder application to the wound. Surgical Technique All rabbit tissues were used within 24 h of sacrifice and were stored at 4 C. Access to the cervical trachea was achieved through a Kocher incision, and a transverse tracheotomy was performed between the first and second tracheal rings. In all studies, the pediatric endotracheal tube was inserted into the proximal trachea and secured in an airtight fashion according to the methods described in the burst threshold manometry section. For the lung parenchymal studies, the skin over the anterior thoracic wall was removed. An incision was made through the fifth intercostal space at the midaxillary line, taking care not to injure the visceral pleura or underlying lung tissue. The contralateral main stem bronchus was then cross-clamped through the thoracotomy to pneumatically isolate the ipsilateral lung. The parenchymal injury was created via a stab incision using a fresh #15 blade. The injury was repaired according to its experimental condition with either 1 ml of fibrin glue or 1 ml of chitosan-based solder. The solder was lased until a characteristic green-to-beige transition occurred ( Fig 2 ). For the tracheal studies, the trachea was resected in its entirety from the thorax and tested in an ex vivo fashion. The endotracheal tube was secured as previously described and the distal trachea was cross-clamped immediately proximal to the carina. In the membranous injury condition, a 5-mm vertical membranous tra- cheal injury was created using a #15 blade. In the cartilaginous injury condition, a 5-mm transverse injury was created through a tracheal ring. In the cartilaginous defect, a mm tracheal window was created through the anterior trachea. Statistical Analysis All statistical analyses were performed using SigmaStat, version 3.1 (Systat Software; San Jose, CA). The burst pressure and total lasing time data were compared using a two-tailed, paired Student t test. Lung Parenchymal Injury Results The mean physiologic baseline burst threshold in all conditions was mm Hg. The burst threshold of the LTW condition ( mm Hg) was not significantly different from that of the baseline burst threshold. The burst threshold of the fibrin glue condition ( mm Hg) was not significantly different from that of the unrepaired condition ( mm Hg). The burst threshold of the LTW condition was significantly higher than that of both the fibrin glue and the unrepaired conditions ( P and P,.001, respectively). The results of each condition were also calculated as a percentage recovery of the burst threshold of the intact lung ( Fig 3 ). Tracheal Injury The injuries repaired using the chitosan-based solder were all significantly stronger than their unrepaired counterparts. The burst strength of the membranous injury repair was mm Hg vs mm Hg in the unrepaired injury ( P,.001). The burst strength of the cartilaginous injury repair was mm Hg vs mm Hg in the unrepaired injury ( P,.001). The burst strength of the cartilaginous defect repair Figure 2. Surgical approach demonstrating a right lateral thoracotomy with lung exposure ( A ). Lased solder (S) seen on the surface of the lung parenchyma ( B ). Image of the solder (S) adherent to the underlying lung tissue (hematoxylin-eosin, original magnification 325) (C ). CHEST / 138 / 2 / AUGUST,

4 Figure 3. Percentage recovery of physiologic baseline lung burst threshold in each repair condition. The percentage of baseline burst threshold in the laser tissue welding condition is significantly greater than that of the fibrin glue or unrepaired conditions ( P,.001). * 5 statistically significant result; LTW 5 laser tissue welding. was mm Hg vs mm Hg in the unrepaired injury ( P,.001). The burst strength of the membranous injury repair was significantly stronger than that of the cartilaginous injury repair ( P 5.03) but was not significantly different from that of the cartilaginous defect repair. The burst pressure of the cartilaginous repair using the chitosan-based solder was significantly higher than that of the same repair using the hyaluronic acid-based solder ( mm Hg vs mm Hg, P,.001). The total lasing time required by the chitosan-based solder was significantly shorter than that of the hyaluronic acid-based solder ( s vs s, P,.001). Discussion Management of airway injury (tracheobroncial injury or persistent pulmonary air leak) in disease or trauma (eg, in the setting of thoracic surgery, spontaneous pneumothorax, advanced-stage emphysema, or malignancy) remains a challenging clinical problem. The need for prolonged chest tube drainage and subsequent impaired mobility leads to longer hospital stays and an increased incidence of associated complications.4 As a result, a variety of techniques have been advocated to help promote closure of these leaks and improve patient outcomes. The principal strategy in the closure of disrupted airway (pulmonary parenchymal air leaks or tracheobronchial injuries) is to use a mechanical means to obstruct airflow while allowing the tissue to seal through innate wound-healing mechanisms. In the case of spontaneous pneumothorax, thoracoscopic bullectomy followed by a pleural adhesion procedure (pleurectomy 6 pleurodesis) is currently recognized as the gold standard technique. 2 Pleurodesis, however, by definition, requires the induction of an inflammatory response through chemical or mechanical means and therefore leads to a significant incidence of postoperative pyrexia and chest pain. Despite this, it may still be associated with a 12% recurrence rate. 7 Similarly, treatment of bronchopleural fistula relies on the identification and mechanical closure of the bronchial defect. Even with approaches that use sutures, staples, and autologous vascularized tissue transfers (flaps), the repairs may fail and patients may experience recurrence rates of 5% to 20%. 3,8 The challenges of the limited success of traditional wound-closure techniques in friable lung parenchyma have catalyzed multiple investigations into the use of tissue adhesives as an adjunctive method of air-leak closure. Although the use of a variety of sealants has been reported, 3,9 fibrin glue has been studied the most extensively. Cho et al 2 reported using fibrin glue in combination with cellulose mesh for staple line coverage in the treatment of spontaneous pneumothorax and found a 5% recurrence rate. Similarly, Kinoshita et al 7 injected fibrin glue into the intrapleural space for the treatment of high-risk patients with pneumothorax. In order to achieve adequate coverage, the authors were forced to create a fourfold dilution, which was associated with a 66% decrease in overall adhesive strength, leading to a failure rate of 12.5%. Hollaus et al 9 looked retrospectively at bronchoscopically guided fibrin glue-assisted closure of bronchopleural fistulae and found a 12.2% recurrence rate. This paper also noted that defects. 8 mm could not be adequately addressed endoscopically. Although the use of fibrin glue has improved the success rate of persistent air-leak closure, the aforementioned reported failure rates and lack of consensus over an optimal approach underscore the fact that this issue remains an active clinical problem. The purpose of this study was to examine an alternative method of air-leak closure using LTW of an albumin-based tissue sealant. Prior studies in the digestive tract have demonstrated that LTW can produce wound repairs capable of withstanding supraphysiologic pressures; 10 however, the behavior of LTW in pulmonary parenchymal and tracheobronchial injured tissue has yet to be fully examined. An equivalent performance would imply that this technology could theoretically be used in a variety of clinical scenarios, including external or iatrogenic trauma, tumor erosion, failed surgical closure of the airway at the time of resection, reoperative surgery, or spontaneous pneumothorax/ruptured bleb. The results of our lung parenchymal injury arm confirmed that the lased wounds were capable of withstanding twice the pressure of the fibrin glue repairs. LTW can be performed endoscopically via a quartz silica fiberoptic cable and therefore one of the aims of 348 Original Research

5 this study was to assess the efficacy of these wound repairs for bronchoscopic treatment of tracheal and/or bronchial injuries. Although the membranous tracheal repair achieved the greatest burst strength, it was not significantly higher than that of the cartilaginous defect repair. The ability of the solder to bind to cartilage and to bridge significant tissue gaps implies that this technology may be used to close larger bronchial defects than those previously reported with other tissue glues. 9 The final aim of this study was to compare the performance of two different solder-gelling agents in the closure of a cartilaginous defect. The viscoelastic and lasing properties of the albumin-based solder are highly dependent on the gelling agent used, and our results confirmed that the chitosan-based solder produced tissue bonds that were significantly stronger than those of the hyaluronic acid-based solder. This finding, coupled with the improvement in total lasing time, indicates that the chitosan-based formula is a superior solder for use in tracheobronchial LTW. Conclusions Injury to the aerodigestive tract (esophageal perforation, tracheobronchial injury, and/or persistent pulmonary air leaks) remains a challenging problem in chest medicine and thoracic surgery in general, especially in high-risk patient populations. In some studies, the introduction of tissue sealants such as fibrin glue, via both endoscopic and open application routes, has been demonstrated to reduce the time to resolution of the injury. 2-4 However, improved clinical outcomes have not been demonstrated uniformly, possibly because of innate limitations in the adhesive strength of fibrin glues. LTW offers the ability to produce endoscopic wound repairs with burst strengths more than twice those of fibrin glue. This study confirmed the feasibility and efficacy of LTW in cadaveric lung and tracheobronchial tissue. Further in vivo animal and clinical studies are needed to characterize the use of LTW to reduce the morbidity of interruptions in aerodigestive-tract integrity in clinical practice settings. Acknowledgments Author contributions: Dr Bleier: contributed to design and execution of experimental plan and drafting of the manuscript. Dr N. M. Cohen: contributed to design and execution of experimental Dr Bloom: contributed to design and execution of experimental Dr Palmer: contributed to design and execution of experimental Dr N. A. Cohen: contributed to design and execution of experimental Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Bleier, Palmer, and N. A. Cohen are coinventors of the chitosan-based solder referenced in the body of the text and are thus entitled to royalties derived from the licensing of a nonprovisional US patent owned by the University of Pennsylvania. Drs N. M. Cohen and Bloom have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: This work was performed at the University of Philadelphia, Philadelphia, Pennsylvania. References 1. Bleier BS, Palmer JN, Gratton MA, Cohen NA. In vivo laser tissue welding in the rabbit maxillary sinus. Am J Rhinol ; 22 (6): Cho S, Huh DM, Kim BH, et al. Staple line covering procedure after thoracoscopic bullectomy for the management of primary spontaneous pneumothorax. Thorac Cardiovasc Surg ;56(4): Lois M, Noppen M. Bronchopleural fistulas: an overview of the problem with special focus on endoscopic management. Chest ;128(6): Moser C, Opitz I, Zhai W, et al. Autologous fibrin sealant reduces the incidence of prolonged air leak and duration of chest tube drainage after lung volume reduction surgery: a prospective randomized blinded study. J Thorac Cardiovasc Surg ;136(4): Kobayashi H, Sekine T, Nakamura T, Shimizu Y. In vivo evaluation of a new sealant material on a rat lung air leak model. J Biomed Mater Res ;58(6): Kirsch AJ, Miller MI, Hensle TW, et al. Laser tissue soldering in urinary tract reconstruction: first human experience. Urology ;46(2): Kinoshita T, Miyoshi S, Katoh M, et al. Intrapleural administration of a large amount of diluted fibrin glue for intractable pneumothorax. Chest ;117(3): Sonobe M, Nakagawa M, Ichinose M, Ikegami N, Nagasawa M, Shindo T. Analysis of risk factors in bronchopleural fistula after pulmonary resection for primary lung cancer. Eur J Cardiothorac Surg ;18(5): Hollaus PH, Lax F, Janakiev D, et al. Endoscopic treatment of postoperative bronchopleural fistula: experience with 45 cases. Ann Thorac Surg ;66(3): Bleier BS, Gratton MA, Leibowitz JM, Palmer JN, Newman JG, Cohen NA. Laser-welded endoscopic endoluminal repair of iatrogenic esophageal perforation: an animal model. Otolaryngol Head Neck Surg ; 139 ( 5 ): CHEST / 138 / 2 / AUGUST,