- Email: [email protected]
Laser-welded endoscopic endoluminal repair of iatrogenic esophageal perforation: An animal model
Otolaryngology–Head and Neck Surgery (2008) 139, 713-717
ORIGINAL RESEARCH—HEAD AND NECK CANCER
Laser-welded endoscopic endoluminal repair of iatrogenic esophageal perforation: An animal model Benjamin S. Bleier, MD, Michael A. Gratton, PhD, Jason M. Leibowitz, MD, James N. Palmer, MD, Jason G. Newman, MD, and Noam A. Cohen, MD, PhD, Philadelphia, PA OBJECTIVE: To test the feasibility of laser tissue welding (LTW) in creating an endoscopic transluminal repair of esophageal perforation. STUDY DESIGN: Animal model. SUBJECTS AND METHODS: A diode laser was used to create an endoluminal rabbit esophageal perforation repair. Burst pressures were compared with open incision, external suture, and external laser–augmented suture closure. Comparisons were performed five times and analyzed with Kruskal-Wallis analysis of variance and a post hoc Dunn method. RESULTS: The burst threshold of the endoluminal weld (54.78 ⫾ 5.84 mm Hg) was significantly higher than that of the open incision (6.5 ⫾ 1.94 mm Hg) and not significantly different than that of the external suture (37.18 ⫾ 1.97 mm Hg) or the laser-augmented suture group (71.60 ⫾ 7.58 mm Hg). CONCLUSION: Laser welding is a feasible method of creating endoluminal repairs with burst strengths comparable with external suture repair, which may allow a subset of patients to avoid traditional open approaches. This is the first reported animal model of LTW for endoscopic closure of iatrogenic esophageal perforation. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
I
atrogenic esophageal perforation is a potentially morbid complication whose incidence has risen over the past 2 decades secondary to increased rates of diagnostic and therapeutic esophageal endoscopy. Open surgical repair remains the gold standard in management; however, several authors have recently described endoscopic management in select cases using stents or clips. While these interventions have been successful in several small series, they involve application of metallic foreign bodies and typically require eventual removal. We describe a novel animal model for primary, single-stage, transluminal repair of esophageal perforation using a laser tissue welding technology that provides an immediate, watertight closure without the need for foreign body implantation. Iatrogenic injury during esophageal instrumentation accounts for as much as 59 percent of all esophageal perfo-
rations, occurring in 0.03 percent of flexible and 0.11 percent of rigid esophagoscopy.1 Mortality rates have been reported at 4 to 20 percent when treatment is initiated within 24 hours and can double with a delay beyond 48 hours.2,3 These injuries tend to occur at anatomical narrow points including the cricopharyngeus, aortic arch, left mainstem bronchus, and lower esophageal sphincter.1 While primary surgical repair with or without autologous reinforcement remains the gold standard with the lowest reported mortality rates, multiple surgical algorithms based on size and location of the perforation as well as presence of a cervical or thoracic fluid collection have been described.3 In 1997, Altorjay et al4 expanded on the criteria established by Cameron et al5 for nonoperative management, which has traditionally involved broad-spectrum antibiotics, nil per os status for at least 48 to 72 hours, and drainage of fluid collection when appropriate. Even within this population, however, up to 20 percent will develop complications mandating surgical intervention.3 As a result, several authors have described endoscopic approaches in an attempt to seal the perforation with self-expandable metallic stents or hemoclips to prevent extraluminal contamination with its attendant morbidity.6-8 Thus far these interventions have been successful in small, highly selected patient populations. However, the use of stents is limited to small perforations with at least 1 to 2 cm of adjacent intact esophageal mucosa, and the stents must be removed at an average of 4 weeks during a second procedure that carries additional risk.8 Laser tissue welding (LTW) involves application of a protein-based solder doped with a laser-specific chromophore, which fuses tissue edges through extracellular matrix protein denaturation following laser exposure. These welds can be created endoscopically using a flexible fiberoptic cable and have been shown to seal mucosal injuries with bond strengths approximating pressures generated during normal esophageal swallow. In addition, the proteinbased solder has been demonstrated to provide a scaffold for
Received May 19, 2008; revised July 21, 2008; accepted August 5, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.08.006
714
Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
normal wound-healing progression while obviating the need for foreign body implantation or additional surgery for removal.9 To our knowledge, this is the first study to attempt an endoluminal repair of esophageal perforation using LTW and to compare the burst strength of these welds to both suture alone and laser-reinforced external suture closure.
METHODS Laser System We used a diode laser module (Iridex, Mountain View, CA), coupled with a quartz silica fiberoptic cable with a 600-m core diameter, according to the following specifications: power 0.5W, pulse duration 0.5s, pulse interval 0.1s, power density 15.9 W/cm2, fluency 8.0 J/cm2, major wavelength output 808 ⫾ 1 nm.
degree pediatric endoscope (Karl Storz, Tuttlingen, Germany). The solder was deposited via an 18G needle over the site of the perforation, ensuring that the entirety of the defect was covered. The laser energy was then applied through a 600-m core diameter quartz silica fiberoptic cable. Following injury and repair, the distal end of the esophagus was sealed by using a 3-0 silk suture ligature while the proximal end was attached to the manometry system via the Luer lock.
Sample Size The formula below was used to calculate the sample size for the respective comparisons in this study. This formula was used considering alpha error with z␣ as specified and is based on prior burst threshold data in oropharyngeal mucosa. N ⫽ 共 z ␣兲 ⫻ 2 ⫻ s 2 2
d2
Solder Preparation Preparation of the biological solder is based on previously described techniques.10 The solder comprises a 2:1:2 mixture of 42-percent bovine serum albumin (Fisher Scientific, Pittsburgh, PA), indocyanine green dye (2.5 mg/mL; Sigma-Aldrich, St Louis, MO), and hyaluronic acid sodium (10 mg/mL; Sigma-Aldrich), respectively. The albumin solution is filtered through a 0.2-m pore filter and 200-L aliquots are mixed with 100 L of indocyanine green dye and 200 L of hyaluronic acid. During welding, laser energy is applied to the solder until a characteristic color transition from green to beige occurs.
Rabbit Tissue Harvest Twenty New Zealand White rabbits were sacrificed under an unrelated institutional Institutional Animal Care and Use Committee (IACUC) protocol, and approval was obtained for use of postmortem tissues. A midline incision was made from sternal notch to pubis, followed by a median sternotomy to expose the thoracic esophagus. The tracheoesophageal complex was dissected off the prevertebral fascia and truncated superiorly at the cricopharyngeus and inferiorly at the level of the diaphragm. The esophagus was then dissected off the trachea in its entirety.
Burst Threshold Manometry The manometry system comprises a closed saline-filled system with a traceable manometer (range –776.00 to ⫹776.00 mm Hg; Fisher Scientific) and a 10-cc syringe arranged in parallel; this system uses standard intravenous tubing secured by a Luer lock. Prior to injury, the esophagus was passed over a 3-cc syringe modified by removal of the flange and creation of a 1 ⫻ 1 cm window through the barrel. In all groups a 5-mm full-thickness esophageal injury was created by using a scalpel with a #15 blade. The endoluminal repair was performed through the open end of the syringe while visualization was augmented with a 30-
where z␣ ⫽ value for alpha error [1.96]; s2 ⫽ variance [9]; d ⫽ difference to be detected [5]; and N ⫽ number of subjects per study group. A total of five subjects per study group were selected because our sample size calculation demonstrated a need for three or more subjects for each study group for adequate power. Statistical analysis. All statistical analyses were performed with SigmaStat version 3.1 (Systat Software Inc, San Jose, CA). All groups were compared by using a Kruskal-Wallis one way analysis of variance and a post hoc pairwise multiple-comparison procedure using the Dunn method. The significance level was set at a probability of 0.05. Experimental groups. Our study consisted of testing the burst pressure through an esophageal injury under four conditions including 5-mm open incision, external suture closure using two 5-0 interrupted Prolene stitches, external laser–augmented suture closure, and sutureless endoluminal laser weld. All conditions were tested five times (Fig 1). Histology. Five additional endoluminal welds were harvested and imbedded in paraffin. Standard hematoxylin and eosin staining was performed, and welds were examined by a veterinary histopathologist for collateral thermal tissue injury.
Role of Funding Source None.
RESULTS The maximal pressure achieved in the closed manometry system was 186.4 mm Hg. The average burst threshold was 6.5 mm Hg (N ⫽ 5, SD ⫽ 1.94) in the open incision group
Bleier et al
Laser-welded endoscopic endoluminal repair of . . .
715
Figure 1 Esophageal perforation experimental groups: open incision (A), external suture closure (two 5-0 interrupted Prolene; (B), external laser–augmented suture repair (C), sutureless endoluminal repair (D).
and 37.18 mm Hg (N ⫽ 5, SD ⫽ 1.97) in the external suture group. Among the laser-welding conditions, the external laser–augmented suture group achieved average burst strength of 71.60 mm Hg (N ⫽ 5, SD ⫽ 7.58), whereas the endoluminal group demonstrated an average of 54.78 mm Hg (N ⫽ 5, SD ⫽ 5.84) (Fig 2). The differences in the median values among the treatment groups were all significantly greater than would be expected by chance (Kruskal-Wallis, H ⫽ 17.87, 3 df, P ⬍ 0.001). Post hoc analysis indicated several treatment groups had significantly different burst strengths. The
burst strength of the endoluminal welding group was significantly higher than that of the open incision group (P ⬍ 0.05). The burst strength of the external laser–augmented suture group was significantly higher than that of both the open incision group and the external suture only group (P ⬍ 0.05). There was no statistically significant difference between the endoluminal weld group and the external suture or external laser–augmented suture group. Histological examination of lased coagulum was compared with normal mucosal controls and demonstrated negligible thermal tissue injury (Fig 3).
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Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
Figure 2 Average burst pressures of each experimental group with standard deviations. Burst pressure of external laser–augmented suture group is significantly higher than that of the external suture and open incision groups (P ⬍ 0.05). There was no significant difference between the endoluminal weld group and the external laser–augmented suture group.
DISCUSSION Perforation of the esophagus carries a significant mortality rate that is directly correlated to rapidity of intervention.3 Iatrogenic injury during endoscopic procedures represents a unique clinical scenario because the perforation may be immediately recognized and treated prior to significant mucosal inflammation and extraluminal soilage.11 Under the appropriate conditions, identification of the perforation during endoscopy affords the surgeon the opportunity to attempt an endoluminal intervention without subjecting the patient to a second procedure that may extend the injury secondary to insufflation or direct trauma.3
Recently several authors have described the use of nitinol self-expanding stents or hemoclips to endoscopically seal the site of perforation to avoid traditional open repair.6,8,12 While this represents a viable method of endoscopic closure, it has been performed in only a highly favorable patient population and mandates implantation of metallic foreign bodies that can migrate and result in mucosal erosion. In addition, the stents must be removed at approximately 4 weeks, which requires further esophageal instrumentation in an already weakened area.8 LTW offers an alternative approach to endoluminal perforation repair that mitigates the complications associated with foreign body implantation. The site of perforation may be visualized by dilating the esophagus via rigid esophagoscopy, and both the solder and the fiberoptic cable can be introduced through the lumen of the esophagoscope under endoscopic visualization. While the mechanism of tissue bonding is not completely understood, it is thought to involve a reorganization of extracellular matrix proteins. LTW has been studied in a variety of tissues including blood vessels, skin, dura, bladder, and urethra.9 These studies have consistently confirmed that LTW is an efficacious method of tissue bonding, and that it is capable of creating instant bonds with significant burst strength that act as a scaffold, allowing for mature scar formation, and enable vascular ingrowth.13 Several authors have described LTW as a method to primarily close or augment suture closure in external esophageal repair14-16; however, this is first report of an animal model for an endoscopic transluminal repair. Our study used an 808-nm diode laser coupled with a 42-percent albumin solder because this laser platform has been the most extensively studied in recent reports. Our use of bovine serum albumin is consistent with prior animal studies; however,
Figure 3 Hematoxylin and eosin images (original magnification: ⫻10) of lased coagulum overlying esophageal mucosa (A) demonstrating minimal thermal injury compared with normal mucosa (B).
Bleier et al
Laser-welded endoscopic endoluminal repair of . . .
for the purposes of future human trials, this substance would be replaced with recombinant human albumin. While our external laser–augmented suture closure achieved a higher mean burst strength (71.6 mm Hg, N ⫽ 5, SD ⫽ 7.58) than that in the sutureless endoluminal group (54.78 mm Hg, N ⫽ 5, SD ⫽ 5.84), these differences did not achieve statistical significance. Furthermore, the normative values for esophageal pressures generated during liquid swallowing are reported at ⱖ30 mm Hg at 5 and 10 cm above the lower esophageal sphincter (LES), with a normal upper limit of LES residual pressure of 11.7 mm Hg.17 Thus, it is likely that the endoluminal weld could withstand both normal resting esophageal tone as well as the weak peristaltic pressure waves generated by swallowing secretions. One of the initial concerns over LTW involved the risk of collateral thermal leakage during laser irradiation. Following the introduction of wavelength-specific chromophores however, laser power density has been reduced to a point in which native tissue is relatively unaffected by laser exposure.9 This is supported by our histological findings that the esophageal mucosa adjacent to the laser weld demonstrated negligible thermal injury.
CONCLUSION This is the first study to attempt and successfully demonstrate the feasibility of using LTW to create a watertight endoluminal repair of an esophageal injury in an animal model without the need for foreign body implantation. Further in vivo studies are required because results may vary in live tissue; however, this technology has the potential to reduce the percentage of patients requiring open surgical repair in the setting of iatrogenic perforation. As with other previously described endoscopic approaches, appropriate patient selection and close observation remain the cornerstones of treatment of this challenging clinical scenario.
ACKNOWLEDGEMENTS The authors would like to thank Iridex (Mountain View, CA) for aid in acquisition and use of the diode laser module.
AUTHOR INFORMATION From the Department of Otorhinolaryngology–Head and Neck Surgery, Hospital of the University of Pennsylvania. Corresponding author: Benjamin S. Bleier, MD, UPHS Department of ORL:HNS, 3400 Spruce St, 5 Ravdin, Philadelphia, PA 19104-4206. E-mail address: [email protected]. This paper was accepted for a poster presentation at Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Chicago, Illinois, September 21-24, 2008.
717
AUTHOR CONTRIBUTIONS Benjamin S. Bleier: data acquisition, manuscript preparation; Michael Anne Gratton: statistics, manuscript preparation; Jason M. Leibowitz: data acquisition, manuscript preparation; James N. Palmer: manuscript preparation; Jason G. Newman: manuscript preparation; Noam A. Cohen: data acquisition, manuscript preparation.
FINANCIAL DISCLOSURES Benjamin S. Bleier: none; Michael Anne Gratton: none; Jason M. Leibowitz: none; James N. Palmer: speaker’s bureau: GEMSNAV, Gyrus-ACMI, MDT-Xomed, Pri-Cara, sanofi-aventis; speaker’s bureau (UTI), consultant: Ortho-McNeil; Jason G. Newman: none; Noam A. Cohen: consultant: MDT-Xomed, Schering Plough.
REFERENCES 1. Wu JT, Mattox KL, Wall MJ Jr. Esophageal perforations: new perspectives and treatment paradigms. J Trauma 2007;63:1173– 84. 2. Port JL, Kent MS, Korst RJ, et al. Thoracic esophageal perforations: a decade of experience. Ann Thoracic Surg. 2003;75:1071– 4. 3. Brinster CJ, Singhal S, Lee L, et al. Evolving options in the management of esophageal perforation. Ann Thoracic Surg 2004;77:1475– 83. 4. Altorjay A, Kiss J, Voros A, et al. Nonoperative management of esophageal perforations. Is it justified? Ann Surg 1997;225:415–21. 5. Cameron JL, Kieffer RF, Hendrix TR, et al. Selective nonoperative management of contained intrathoracic esophageal disruptions. Ann Thoracic Surg 1979;27:404 – 8. 6. Fischer A, Schrag HJ, Goos M, et al. Nonoperative treatment of four esophageal perforations with hemostatic clips. Dis Esophagus 2007; 20:444 – 8. 7. Sung HY, Kim JI, Cheung DY, et al. Successful endoscopic hemoclipping of an esophageal perforation. Dis Esophagus 2007;20: 449 –52. 8. Fischer A, Thomusch O, Benz S, et al. Nonoperative treatment of 15 benign esophageal perforations with self-expandable covered metal stents. Ann Thoracic Surg 2006;81:467–72. 9. Bleier BS, Palmer JN, Sparano AM, et al. Laser-assisted cerebrospinal fluid leak repair: an animal model to test feasibility. Otolaryngol Head Neck Surg 2007;137:810 – 4. 10. Kirsch AJ, Miller MI, Hensle TW, et al. Laser tissue soldering in urinary tract reconstruction: first human experience. Urology 1995;46: 261– 6. 11. Wesdorp IC, Bartelsman JF, Huibregtse K, et al. Treatment of instrumental oesophageal perforation. Gut 1984;25:398 – 404. 12. Qadeer MA, Dumot JA, Vargo JJ, et al. Endoscopic clips for closing esophageal perforations: case report and pooled analysis. Gastrointest Endosc 2007;66:605–11. 13. Simhon D, Brosh T, Halpern M, et al. Closure of skin incisions in rabbits by laser soldering: I: Wound healing pattern. Lasers Surg Med 2004;35:1–11. 14. Eby PL, Branfman GS, Ruiz-Razura A, et al. CO2 laser-assisted repair of esophageal lacerations. J Reconstr Microsurg 1992;8:293– 6. 15. Nageris BI, Zilker Z, Zilker M, et al. Esophageal incisions repair by CO2 laser soldering. Otolaryngol Head Neck Surg 2004;131:856 –9. 16. Auteri JS, Oz MC, Jeevanandam V, et al. Laser activation of tissue sealant in hand-sewn canine esophageal closure. J Thorac Cardiovasc Surg 1992;103:781–3. 17. Blonski W, Vela M, Hila A, et al. Normal values for manometry performed with swallows of viscous test material. Scand J Gastroenterol 2008;43:155– 60.
ORIGINAL RESEARCH—HEAD AND NECK CANCER
Laser-welded endoscopic endoluminal repair of iatrogenic esophageal perforation: An animal model Benjamin S. Bleier, MD, Michael A. Gratton, PhD, Jason M. Leibowitz, MD, James N. Palmer, MD, Jason G. Newman, MD, and Noam A. Cohen, MD, PhD, Philadelphia, PA OBJECTIVE: To test the feasibility of laser tissue welding (LTW) in creating an endoscopic transluminal repair of esophageal perforation. STUDY DESIGN: Animal model. SUBJECTS AND METHODS: A diode laser was used to create an endoluminal rabbit esophageal perforation repair. Burst pressures were compared with open incision, external suture, and external laser–augmented suture closure. Comparisons were performed five times and analyzed with Kruskal-Wallis analysis of variance and a post hoc Dunn method. RESULTS: The burst threshold of the endoluminal weld (54.78 ⫾ 5.84 mm Hg) was significantly higher than that of the open incision (6.5 ⫾ 1.94 mm Hg) and not significantly different than that of the external suture (37.18 ⫾ 1.97 mm Hg) or the laser-augmented suture group (71.60 ⫾ 7.58 mm Hg). CONCLUSION: Laser welding is a feasible method of creating endoluminal repairs with burst strengths comparable with external suture repair, which may allow a subset of patients to avoid traditional open approaches. This is the first reported animal model of LTW for endoscopic closure of iatrogenic esophageal perforation. © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
I
atrogenic esophageal perforation is a potentially morbid complication whose incidence has risen over the past 2 decades secondary to increased rates of diagnostic and therapeutic esophageal endoscopy. Open surgical repair remains the gold standard in management; however, several authors have recently described endoscopic management in select cases using stents or clips. While these interventions have been successful in several small series, they involve application of metallic foreign bodies and typically require eventual removal. We describe a novel animal model for primary, single-stage, transluminal repair of esophageal perforation using a laser tissue welding technology that provides an immediate, watertight closure without the need for foreign body implantation. Iatrogenic injury during esophageal instrumentation accounts for as much as 59 percent of all esophageal perfo-
rations, occurring in 0.03 percent of flexible and 0.11 percent of rigid esophagoscopy.1 Mortality rates have been reported at 4 to 20 percent when treatment is initiated within 24 hours and can double with a delay beyond 48 hours.2,3 These injuries tend to occur at anatomical narrow points including the cricopharyngeus, aortic arch, left mainstem bronchus, and lower esophageal sphincter.1 While primary surgical repair with or without autologous reinforcement remains the gold standard with the lowest reported mortality rates, multiple surgical algorithms based on size and location of the perforation as well as presence of a cervical or thoracic fluid collection have been described.3 In 1997, Altorjay et al4 expanded on the criteria established by Cameron et al5 for nonoperative management, which has traditionally involved broad-spectrum antibiotics, nil per os status for at least 48 to 72 hours, and drainage of fluid collection when appropriate. Even within this population, however, up to 20 percent will develop complications mandating surgical intervention.3 As a result, several authors have described endoscopic approaches in an attempt to seal the perforation with self-expandable metallic stents or hemoclips to prevent extraluminal contamination with its attendant morbidity.6-8 Thus far these interventions have been successful in small, highly selected patient populations. However, the use of stents is limited to small perforations with at least 1 to 2 cm of adjacent intact esophageal mucosa, and the stents must be removed at an average of 4 weeks during a second procedure that carries additional risk.8 Laser tissue welding (LTW) involves application of a protein-based solder doped with a laser-specific chromophore, which fuses tissue edges through extracellular matrix protein denaturation following laser exposure. These welds can be created endoscopically using a flexible fiberoptic cable and have been shown to seal mucosal injuries with bond strengths approximating pressures generated during normal esophageal swallow. In addition, the proteinbased solder has been demonstrated to provide a scaffold for
Received May 19, 2008; revised July 21, 2008; accepted August 5, 2008.
0194-5998/$34.00 © 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. doi:10.1016/j.otohns.2008.08.006
714
Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
normal wound-healing progression while obviating the need for foreign body implantation or additional surgery for removal.9 To our knowledge, this is the first study to attempt an endoluminal repair of esophageal perforation using LTW and to compare the burst strength of these welds to both suture alone and laser-reinforced external suture closure.
METHODS Laser System We used a diode laser module (Iridex, Mountain View, CA), coupled with a quartz silica fiberoptic cable with a 600-m core diameter, according to the following specifications: power 0.5W, pulse duration 0.5s, pulse interval 0.1s, power density 15.9 W/cm2, fluency 8.0 J/cm2, major wavelength output 808 ⫾ 1 nm.
degree pediatric endoscope (Karl Storz, Tuttlingen, Germany). The solder was deposited via an 18G needle over the site of the perforation, ensuring that the entirety of the defect was covered. The laser energy was then applied through a 600-m core diameter quartz silica fiberoptic cable. Following injury and repair, the distal end of the esophagus was sealed by using a 3-0 silk suture ligature while the proximal end was attached to the manometry system via the Luer lock.
Sample Size The formula below was used to calculate the sample size for the respective comparisons in this study. This formula was used considering alpha error with z␣ as specified and is based on prior burst threshold data in oropharyngeal mucosa. N ⫽ 共 z ␣兲 ⫻ 2 ⫻ s 2 2
d2
Solder Preparation Preparation of the biological solder is based on previously described techniques.10 The solder comprises a 2:1:2 mixture of 42-percent bovine serum albumin (Fisher Scientific, Pittsburgh, PA), indocyanine green dye (2.5 mg/mL; Sigma-Aldrich, St Louis, MO), and hyaluronic acid sodium (10 mg/mL; Sigma-Aldrich), respectively. The albumin solution is filtered through a 0.2-m pore filter and 200-L aliquots are mixed with 100 L of indocyanine green dye and 200 L of hyaluronic acid. During welding, laser energy is applied to the solder until a characteristic color transition from green to beige occurs.
Rabbit Tissue Harvest Twenty New Zealand White rabbits were sacrificed under an unrelated institutional Institutional Animal Care and Use Committee (IACUC) protocol, and approval was obtained for use of postmortem tissues. A midline incision was made from sternal notch to pubis, followed by a median sternotomy to expose the thoracic esophagus. The tracheoesophageal complex was dissected off the prevertebral fascia and truncated superiorly at the cricopharyngeus and inferiorly at the level of the diaphragm. The esophagus was then dissected off the trachea in its entirety.
Burst Threshold Manometry The manometry system comprises a closed saline-filled system with a traceable manometer (range –776.00 to ⫹776.00 mm Hg; Fisher Scientific) and a 10-cc syringe arranged in parallel; this system uses standard intravenous tubing secured by a Luer lock. Prior to injury, the esophagus was passed over a 3-cc syringe modified by removal of the flange and creation of a 1 ⫻ 1 cm window through the barrel. In all groups a 5-mm full-thickness esophageal injury was created by using a scalpel with a #15 blade. The endoluminal repair was performed through the open end of the syringe while visualization was augmented with a 30-
where z␣ ⫽ value for alpha error [1.96]; s2 ⫽ variance [9]; d ⫽ difference to be detected [5]; and N ⫽ number of subjects per study group. A total of five subjects per study group were selected because our sample size calculation demonstrated a need for three or more subjects for each study group for adequate power. Statistical analysis. All statistical analyses were performed with SigmaStat version 3.1 (Systat Software Inc, San Jose, CA). All groups were compared by using a Kruskal-Wallis one way analysis of variance and a post hoc pairwise multiple-comparison procedure using the Dunn method. The significance level was set at a probability of 0.05. Experimental groups. Our study consisted of testing the burst pressure through an esophageal injury under four conditions including 5-mm open incision, external suture closure using two 5-0 interrupted Prolene stitches, external laser–augmented suture closure, and sutureless endoluminal laser weld. All conditions were tested five times (Fig 1). Histology. Five additional endoluminal welds were harvested and imbedded in paraffin. Standard hematoxylin and eosin staining was performed, and welds were examined by a veterinary histopathologist for collateral thermal tissue injury.
Role of Funding Source None.
RESULTS The maximal pressure achieved in the closed manometry system was 186.4 mm Hg. The average burst threshold was 6.5 mm Hg (N ⫽ 5, SD ⫽ 1.94) in the open incision group
Bleier et al
Laser-welded endoscopic endoluminal repair of . . .
715
Figure 1 Esophageal perforation experimental groups: open incision (A), external suture closure (two 5-0 interrupted Prolene; (B), external laser–augmented suture repair (C), sutureless endoluminal repair (D).
and 37.18 mm Hg (N ⫽ 5, SD ⫽ 1.97) in the external suture group. Among the laser-welding conditions, the external laser–augmented suture group achieved average burst strength of 71.60 mm Hg (N ⫽ 5, SD ⫽ 7.58), whereas the endoluminal group demonstrated an average of 54.78 mm Hg (N ⫽ 5, SD ⫽ 5.84) (Fig 2). The differences in the median values among the treatment groups were all significantly greater than would be expected by chance (Kruskal-Wallis, H ⫽ 17.87, 3 df, P ⬍ 0.001). Post hoc analysis indicated several treatment groups had significantly different burst strengths. The
burst strength of the endoluminal welding group was significantly higher than that of the open incision group (P ⬍ 0.05). The burst strength of the external laser–augmented suture group was significantly higher than that of both the open incision group and the external suture only group (P ⬍ 0.05). There was no statistically significant difference between the endoluminal weld group and the external suture or external laser–augmented suture group. Histological examination of lased coagulum was compared with normal mucosal controls and demonstrated negligible thermal tissue injury (Fig 3).
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Otolaryngology–Head and Neck Surgery, Vol 139, No 5, November 2008
Figure 2 Average burst pressures of each experimental group with standard deviations. Burst pressure of external laser–augmented suture group is significantly higher than that of the external suture and open incision groups (P ⬍ 0.05). There was no significant difference between the endoluminal weld group and the external laser–augmented suture group.
DISCUSSION Perforation of the esophagus carries a significant mortality rate that is directly correlated to rapidity of intervention.3 Iatrogenic injury during endoscopic procedures represents a unique clinical scenario because the perforation may be immediately recognized and treated prior to significant mucosal inflammation and extraluminal soilage.11 Under the appropriate conditions, identification of the perforation during endoscopy affords the surgeon the opportunity to attempt an endoluminal intervention without subjecting the patient to a second procedure that may extend the injury secondary to insufflation or direct trauma.3
Recently several authors have described the use of nitinol self-expanding stents or hemoclips to endoscopically seal the site of perforation to avoid traditional open repair.6,8,12 While this represents a viable method of endoscopic closure, it has been performed in only a highly favorable patient population and mandates implantation of metallic foreign bodies that can migrate and result in mucosal erosion. In addition, the stents must be removed at approximately 4 weeks, which requires further esophageal instrumentation in an already weakened area.8 LTW offers an alternative approach to endoluminal perforation repair that mitigates the complications associated with foreign body implantation. The site of perforation may be visualized by dilating the esophagus via rigid esophagoscopy, and both the solder and the fiberoptic cable can be introduced through the lumen of the esophagoscope under endoscopic visualization. While the mechanism of tissue bonding is not completely understood, it is thought to involve a reorganization of extracellular matrix proteins. LTW has been studied in a variety of tissues including blood vessels, skin, dura, bladder, and urethra.9 These studies have consistently confirmed that LTW is an efficacious method of tissue bonding, and that it is capable of creating instant bonds with significant burst strength that act as a scaffold, allowing for mature scar formation, and enable vascular ingrowth.13 Several authors have described LTW as a method to primarily close or augment suture closure in external esophageal repair14-16; however, this is first report of an animal model for an endoscopic transluminal repair. Our study used an 808-nm diode laser coupled with a 42-percent albumin solder because this laser platform has been the most extensively studied in recent reports. Our use of bovine serum albumin is consistent with prior animal studies; however,
Figure 3 Hematoxylin and eosin images (original magnification: ⫻10) of lased coagulum overlying esophageal mucosa (A) demonstrating minimal thermal injury compared with normal mucosa (B).
Bleier et al
Laser-welded endoscopic endoluminal repair of . . .
for the purposes of future human trials, this substance would be replaced with recombinant human albumin. While our external laser–augmented suture closure achieved a higher mean burst strength (71.6 mm Hg, N ⫽ 5, SD ⫽ 7.58) than that in the sutureless endoluminal group (54.78 mm Hg, N ⫽ 5, SD ⫽ 5.84), these differences did not achieve statistical significance. Furthermore, the normative values for esophageal pressures generated during liquid swallowing are reported at ⱖ30 mm Hg at 5 and 10 cm above the lower esophageal sphincter (LES), with a normal upper limit of LES residual pressure of 11.7 mm Hg.17 Thus, it is likely that the endoluminal weld could withstand both normal resting esophageal tone as well as the weak peristaltic pressure waves generated by swallowing secretions. One of the initial concerns over LTW involved the risk of collateral thermal leakage during laser irradiation. Following the introduction of wavelength-specific chromophores however, laser power density has been reduced to a point in which native tissue is relatively unaffected by laser exposure.9 This is supported by our histological findings that the esophageal mucosa adjacent to the laser weld demonstrated negligible thermal injury.
CONCLUSION This is the first study to attempt and successfully demonstrate the feasibility of using LTW to create a watertight endoluminal repair of an esophageal injury in an animal model without the need for foreign body implantation. Further in vivo studies are required because results may vary in live tissue; however, this technology has the potential to reduce the percentage of patients requiring open surgical repair in the setting of iatrogenic perforation. As with other previously described endoscopic approaches, appropriate patient selection and close observation remain the cornerstones of treatment of this challenging clinical scenario.
ACKNOWLEDGEMENTS The authors would like to thank Iridex (Mountain View, CA) for aid in acquisition and use of the diode laser module.
AUTHOR INFORMATION From the Department of Otorhinolaryngology–Head and Neck Surgery, Hospital of the University of Pennsylvania. Corresponding author: Benjamin S. Bleier, MD, UPHS Department of ORL:HNS, 3400 Spruce St, 5 Ravdin, Philadelphia, PA 19104-4206. E-mail address: [email protected]. This paper was accepted for a poster presentation at Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Chicago, Illinois, September 21-24, 2008.
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AUTHOR CONTRIBUTIONS Benjamin S. Bleier: data acquisition, manuscript preparation; Michael Anne Gratton: statistics, manuscript preparation; Jason M. Leibowitz: data acquisition, manuscript preparation; James N. Palmer: manuscript preparation; Jason G. Newman: manuscript preparation; Noam A. Cohen: data acquisition, manuscript preparation.
FINANCIAL DISCLOSURES Benjamin S. Bleier: none; Michael Anne Gratton: none; Jason M. Leibowitz: none; James N. Palmer: speaker’s bureau: GEMSNAV, Gyrus-ACMI, MDT-Xomed, Pri-Cara, sanofi-aventis; speaker’s bureau (UTI), consultant: Ortho-McNeil; Jason G. Newman: none; Noam A. Cohen: consultant: MDT-Xomed, Schering Plough.
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