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.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
tracheal stenosis; subglottic stenosis; rigid bronchoscopy; mitomycin C; endotracheal intubation