Madan, Karan MD, DM; Agarwal, Ritesh MD, DM; Aggarwal, Ashutosh N. MD, DM; Gupta, Dheeraj MD, DM
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Disclosure: There is no conflict of interest or other disclosures.
Reprints: Ritesh Agarwal, MD, DM, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India (e-mail: email@example.com; firstname.lastname@example.org)
Received July 2, 2012
Accepted August 30, 2012
Background: Postintubation tracheal stenosis (PITS) is a common problem encountered by interventional pulmonologists. The aim of this study was to evaluate the utility of mitomycin C (MMC) as an adjunctive treatment to rigid bronchoscopic dilatation in patients with PITS.
Methods: Prospective analysis of data from the interventional pulmonology unit of a large tertiary care teaching center in North India. Patients with a diagnosis of PITS undergoing rigid bronchoscopic dilatation and MMC (0.4 mg/mL) application were included. The primary outcome was the occurrence of restenosis.
Results: Seven patients underwent rigid bronchoscopic dilatation, followed by the application of MMC at 4 quadrants of the stenosis. Controlled radial expansion balloon bronchoplasty was also performed, if necessary, in addition to mechanical dilatation using the barrel of the rigid bronchoscope. Restenosis occurred in all 7 patients (100%) and the mean duration to the detection of restenosis was 27 days. The restenosis was symptomatic in 6 out of 7 (85.7%) patients.
Conclusions: Rigid bronchoscopic dilatation and a single application of MMC is not an effective treatment in the management of PITS.
With advances in intensive care, an ever-increasing number of critically ill patients are being cared for worldwide. This has increased the risk of complications associated with prolonged endotracheal intubation and tracheostomy. As a result, a growing number of patients with postintubation tracheal stenosis (PITS) are being encountered by interventional pulmonologists.1 The aim of the treatment in PITS is to ensure an airway diameter that is adequate to allow ventilation and relief of symptoms. A myriad of techniques have been used for the management of these patients including endoscopic bougie dilatation, laser vaporization, tracheal stenting, and tracheal resection with end-to-end anastomosis. Surgical resection and anastomosis is considered the definitive treatment of PITS. However, the surgical facilities and dedicated tracheal surgeons are not routinely available, more so in developing countries. The other limiting factors for surgery include concomitant underlying medical conditions and operability. Surgery has also been reported to be associated with recurrence of stenosis and granulation tissue formation at the site of the anastomosis. Hence, a bronchoscopic intervention is an important complementary therapeutic strategy.2
At our center, rigid bronchoscopic dilatation and tracheal stenting (using a Dumon silicon stent or a silicon Montgomery T-tube for high tracheal or subglottic stenosis) have been the preferred modality in the management of PITS. In some patients in whom the deployment of a tracheal stent is unsuccessful owing to technical and logistic reasons, rigid bronchoscopic dilatation alone is used as a temporary measure. As this has been associated with a high rate of restenosis, we prospectively evaluated patients to assess the utility of adjunctive mitomycin C (MMC) application with rigid bronchoscopic dilatation in the prevention of symptomatic stenosis in patients with PITS, where a silicon stent placement was not performed.
PATIENTS AND METHODS
Patients with symptomatic PITS were eligible for inclusion in the study. A written informed consent was obtained from all patients and the study was approved by the Local Ethics committee. A preanesthesia evaluation was carried out and routine blood investigations were performed including complete blood count, coagulation profile, serum electrolytes, liver and renal function tests, and arterial blood gas analysis. A computed tomography of the neck and thorax was obtained in all patients to localize the site of the stenosis and a flexible bronchoscopic examination was carried out before the rigid bronchoscopic procedure, wherever feasible. The stenosis was graded using the Myers and Cotton classification scheme, which grades the lesion from I to IV, describing stenosis as a percent of area that is obstructed as follows: (i) grade I, 0% to 50% of the lumen obstructed; (ii) grade II, obstruction of 51% to 70% of the lumen; (iii) grade III, 71% to 99% obstruction of the lumen; and (iv) grade IV, no detectable lumen, that is, 100% luminal obstruction.3
All procedures were carried out under total intravenous anesthesia. Patients were preoxygenated for a minimum of 3 minutes to compensate for apnea during rigid bronchoscopic intubation. Induction of anesthesia was performed with intravenous propofol and fentanyl, followed by intravenous succinylcholine to achieve neuromuscular blockade. After intubation with the rigid bronchoscope, patients were maintained with a combination of intravenous propofol and atracurium (or vecuronium) and conventionally ventilated through the ventilation port of the rigid bronchoscope. Reversal of neuromuscular blockade was achieved with neostigmine and glycopyrrolate. Rigid bronchoscopy was performed with 6.5 to 14-mm internal diameter Storz bronchoscopes (Karl Storz GmbH & Co. KG, Germany). Endoscopic magnification was provided by a straight-forward telescope (Hopkins telescope; Karl Storz GmbH & Co. KG) attached to a video monitor to provide visualization for the entire procedure. Stenosis was initially dilated with a size 6.5 barrel using rotatory motion, followed by progressive dilatation with rigid bronchoscopes of increasing sizes. If the stenotic segment could not be manipulated through the rigid bronchoscope, then a rapid balloon bronchoplasty was performed using 5.5-cm length wire-guided balloons (CRE; Boston Scientific) with sequentially larger diameters.
MMC was applied at a concentration of 0.4 mg/mL. A gauze pledget was soaked in a 0.4 mg/mL solution of MMC and applied with pressure at the 4 quadrants of the stenotic segment after rigid bronchoscopic dilatation. The pledgets were grasped with forceps (bronchoscopic forceps alligator, grasping with a double-active jaw) that were introduced into the trachea through the lumen of the rigid bronchoscope. Care was taken not to have circumferential contact or touch the walls of the uninjured trachea. At each quadrant, a 2-minute contact time was allowed. A flexible bronchoscopic examination was scheduled in all patients after 2 weeks after rigid bronchoscopy or performed earlier if clinically indicated because of the presence of symptoms.
Between July 2009 and August 2011, MMC application was used as an adjunct to rigid bronchoscopic dilatation in the management of 7 patients with PITS [pneumonia (n=4), meningitis (n=1), poisoning (n=1), and snakebite (n=1)]. One patient had undergone tracheostomy before the development of symptomatic stenosis. The clinical characteristics of the patients are summarized in Table 1. There were 4 men and 3 women ranging in age from 18 to 43 years. All the patients had Myers and Cotton stage III (>70% stenosis of the lumen) stenotic lesions (Fig. 1). The median (IQR) length of stenosis and the median (IQR) distance from the vocal cords was 16 mm (14 to 18 mm) and 32 mm (28 to 36 mm), respectively. At least 14 mm tracheal luminal patency was achieved after rigid bronchoscopic and/or balloon dilatation before MMC application in all patients.
Restenosis occurred in all the patients. The mean (SD) duration to the detection of restenosis was 27 (8.3) days. The severity of stenosis was Myers and Cotton stage III in 6 patients, whereas 1 patient had a stage I stenotic lesion. Stenosis was symptomatic in 6 of the 7 patients. Only the patient with stage I restenosis was asymptomatic. In 3 of the 6 patients, silicon stent placement was performed on follow-up (tracheal stents in 2 and a Montgomery T-tube in 1). In the remaining 3 patients, a second application of MMC was performed. All the 3 patients again developed symptomatic restenosis on follow-up, and were subsequently referred for surgery.
Since the first recognition of postintubation laryngotracheal injuries in 1969, tracheal stenosis has been considered as an extremely difficult to handle clinical scenario.4 PITS is the most common benign cause of upper airway stenosis in all ages, and occurs in 1% to 4% of patients requiring mechanical ventilation.5 The majority of the symptomatic patients have mature fibrotic circumferential scars. It is not unusual for these patients to be misdiagnosed with asthma,6 and this delay in diagnosis and management leads to a densely scarred stenotic lesion at the time of diagnosis. Tracheal stenosis is known to occur after even a relatively short duration of endotracheal intubation.4
PITS has been termed the “tracheal bedsore”. The proposed mechanism is ischemic necrosis because of the pressure exerted by the endotracheal or the tracheostomy tube cuff on the tracheal mucosa. This subsequently induces the formation of granulation tissue and stenosis at the injured segment. PITS occurs despite the widespread use of high-volume and low-pressure cuffs in most intensive care units.7 The major drawback associated with treatment is the formation of recurrent granulation tissue at the edges of the dilated segment or the margins of the surgically approximated edges. This necessitates repeated interventional bronchoscopic procedures, which themselves may be associated with the formation of granulation tissue. Although tracheal reconstruction is considered the treatment of choice for PTIS, it is a major surgical procedure, with procedure mortality approaching almost 3%.8
MMC is an anthracycline antibiotic isolated from the bacterium Streptomyces caepitocus, and acts as any alkylating agent by inhibiting DNA synthesis.9 It inhibits in vitro fibroblast proliferation and collagen deposition and has been studied in the surgical management of conditions such as pterygium, urothelial tumors, choanal atresia, endoscopic sinus surgery, maxillary antrostomy, and lacrimal duct stenosis.10,11 The role of MMC has also been examined in tracheobronchial stenosis.8,12–15 We carried out a systematic review of the PubMed database using the following search term: mitomycin C AND (“tracheal stenosis” OR “airway stenosis” OR “airway stenoses” OR “airway obstruction”) to analyze the results of MMC in adult (12 y or older) tracheal stenosis. We included studies in which MMC was used as an adjunct to bronchoscopic management. We excluded studies involving <5 patients, pediatric studies, and studies with glottic stenosis and in situations where MMC was used as an adjunct to tracheal surgery.
Our search yielded 7 studies (114 patients),16–22 which are summarized in Table 2. All the studies are from the realm of otolaryngologists who have used laser incisions, specialized equipment such as subglottiscopes, operating microscopes, and other accessories in addition to the use of MMC. There is no consensus on the most appropriate and effective concentration, contact duration, or the frequency of application of MMC. The results are also heterogenous and the only conclusion that can be drawn from these studies is that MMC is variably effective, and at best, can delay the progression of tracheal stenosis. However, the results of our study indicate that MMC application after rigid bronchoscopic dilatation is not an effective modality in the prevention of tracheal restenosis in PITS. Almost all patients developed restenosis after a single application of MMC (0.4 mg/mL). In addition, restenosis was symptomatic in most cases. We used a relatively lower concentration of MMC and did not use laser incisions. However, the tracheal dilatation achieved with mechanical dilatation was at least 14 mm in all patients.
Higher concentrations of MMC (1 mg/mL) have been shown to be beneficial in patients with posttraumatic bronchial stenosis, although argon photocoagulation was used as an adjunct during the bronchoscopic dilatation.11 In clinical studies, concentrations ranging from 0.1 to 2 mg/mL have been used.12,23 Erard et al12 reported a favorable outcome in a patient with post lung transplant, recurrent main bronchus stenosis using a single application of a 2 mg/mL concentration of MMC. We used a total contact duration of 8 minutes as used by Wong et al.8 The contact duration has ranged from 2 to 5 minutes in different studies. Although most of the studies have investigated a single application of MMC, the utility of two spaced applications has also been explored. Reduced relapse rates at 1 and 3 years have been reported by Smith and Elstad, comparing 2 with a single application of MMC. The relapse rates at 1 and 3 years were 7% and 36% (2 application group) and 33% and 58% (single application group), respectively; however, the 5-year relapse rates were similar (70%).22
One of the key factors involved in the late stages of untreated benign tracheal stenosis is the high-level expression of TGF-β1, which has been shown to counteract the inhibiting effect of MMC on fibroblast proliferation in vitro. This has been proposed as one of the important reasons for the limited treatment effect of MMC in benign tracheal stenosis.24 In a prospective, double-blind, randomized-controlled study that investigated the utility of low-dose (0.2 mg/mL) and high-dose (0.5 mg/mL) MMC versus placebo (isotonic saline) in a rabbit model of tracheal stenosis, MMC was not effective in preventing the percentage decrease in the luminal diameter in either of the groups. In contrast, there was a significant increase in fibroproliferative scar formation in the high-dose group.10 The use of MMC has also been associated with acute airway obstruction when used to prevent tracheal stenosis in a rabbit model of tracheal injury.25
Considering the difficult course of management of patients who develop PITS, Nouraei and colleagues attempted to study whether early detection and intervention in fibroinflammatory lesions in patients after intubation has implications for the patient’s eventual outcome. Using a multimodality approach in patients divided into 2 groups (early and mature airway lesions), they showed that early detection and intervention with intralesional steroids can lead to a long-term favorable outcome in patients with acute fibroinflammatory airway lesions with fewer interventions, the majority requiring a single treatment. The early airway lesion group also had a significantly longer intervention-free interval and did not require external laryngotracheal reconstruction compared with patients treated for mature fibrotic scars with MMC.19
Finally, our study is not without limitations, the major limitations being that it was carried out in a single center and also had a small sample size. Hence, the results need to be validated in a larger sample. Moreover, a higher concentration of MMC, preferably 1 to 2 mg/mL, should be used for better results.
The results of our study fail to show the efficacy of rigid bronchoscopic dilatation and MMC application in patients with PITS. Larger studies are required to confirm or negate our findings.
1. Wain JC Jr. Postintubation tracheal stenosis. Semin Thorac Cardiovasc Surg. 2009;21:284–289
2. Liberman M. Bronchoscopic evaluation of the trachea and dilation of the trachea. Semin Thorac Cardiovasc Surg. 2009;21:255–262
3. Myer CM III, O’Connor DM, Cotton RT. Proposed grading system for subglottic stenosis based on endotracheal tube sizes. Ann Otol Rhinol Laryngol. 1994;103:319–323
4. Lindholm CE. Prolonged endotracheal intubation. Acta Anaesthesiol Scand Suppl. 1970;33:1–131
5. Lorenz RR. Adult laryngotracheal stenosis: etiology and surgical management. Curr Opin Otolaryngol Head Neck Surg. 2003;11:467–472
6. Nagappan R, Parkin G, Wright CA, et al. Adult long-segment tracheal stenosis attributable to complete tracheal rings masquerading as asthma. Crit Care Med. 2002;30:238–240
7. Grillo HCGrillo HC. Postintubation stenosis. Surgery of the Trachea and Bronchi. 2004 Ontario BC Decker Inc.:301–339
8. Wong JL, Tie ST, Samril B, et al. Successful treatment of tracheal stenosis by rigid bronchoscopy and topical mitomycin C: a case report. Cases J. 2010;3:2
9. Rojas-Solano J, Becker HD. Bronchoscopic application of mitomycin-C as adjuvant treatment for benign airway stenosis. J Bronchol Interv Pulmonol. 2011;18:53–55
10. Iniguez-Cuadra R, San Martin Prieto J, Iniguez-Cuadra M, et al. Effect of mitomycin in the surgical treatment of tracheal stenosis. Arch Otolaryngol Head Neck Surg. 2008;134:709–714
11. Daher P, Riachy E, Georges B, et al. Topical application of mitomycin C in the treatment of esophageal and tracheobronchial stricture: a report of 2 cases. J Pediatr Surg. 2007;42:E9–E11
12. Erard AC, Monnier P, Spiliopoulos A, et al. Mitomycin C for control of recurrent bronchial stenosis: a case report. Chest. 2001;120:2103–2105
13. Ferreira S, Nogueira C, Oliveira A, et al. Bronchoscopic dilation techniques and topical application of mitomycin-C in the treatment of tracheal stenosis post intubation—two case reports. Rev Port Pneumol. 2010;16:149–156
14. Teo F, Anantham D, Feller-Kopman D, et al. Bronchoscopic management of sarcoidosis related bronchial stenosis with adjunctive topical mitomycin C. Ann Thorac Surg. 2010;89:2005–2007
15. Cortes de Miguel S, Cabeza Barrera J, Gallardo Medina M, et al. Topical endotracheal mitomycin C as a complementary treatment for endoscopic treatment of recurrent laryngotracheal stenosis. Farm Hosp. 2011;35:32–35
16. Rahbar R, Valdez TA, Shapshay SM. Preliminary results of intraoperative mitomycin-C in the treatment and prevention of glottic and subglottic stenosis. J Voice. 2000;14:282–286
17. Rahbar R, Shapshay SM, Healy GB. Mitomycin: effects on laryngeal and tracheal stenosis, benefits, and complications. Ann Otol Rhinol Laryngol. 2001;110:1–6
18. Perepelitsyn I, Shapshay SM. Endoscopic treatment of laryngeal and tracheal stenosis-has mitomycin C improved the outcome? Otolaryngol Head Neck Surg. 2004;131:16–20
19. Nouraei SA, Singh A, Patel A, et al. Early endoscopic treatment of acute inflammatory airway lesions improves the outcome of postintubation airway stenosis. Laryngoscope. 2006;116:1417–1421
20. Simpson CB, James JC. The efficacy of mitomycin-C in the treatment of laryngotracheal stenosis. Laryngoscope. 2006;116:1923–1925
21. Roediger FC, Orloff LA, Courey MS. Adult subglottic stenosis: management with laser incisions and mitomycin-C. Laryngoscope. 2008;118:1542–1546
22. Smith ME, Elstad M. Mitomycin C and the endoscopic treatment of laryngotracheal stenosis: are two applications better than one? Laryngoscope. 2009;119:272–283
23. Cosano-Povedano J, Muñoz-Cabrera L, Jurado-Gámez B, et al. Topical mitomycin C for recurrent bronchial stenosis after lung transplantation: a report of 2 cases. J Bronchol Interv Pulmonol. 2008;15:281–283
24. Karagiannidis C, Velehorschi V, Obertrifter B, et al. High-level expression of matrix-associated transforming growth factor-beta1 in benign airway stenosis. Chest. 2006;129:1298–1304
25. Roh JL, Kim DH, Rha KS, et al. Benefits and risks of mitomycin use in the traumatized tracheal mucosa. Otolaryngol Head Neck Surg. 2007;136:459–463
© 2012 Lippincott Williams & Wilkins, Inc.