Tracheobronchial stenosis may be caused by either benign or malignant disease. Benign strictures may be caused by sequelae of intubation, resection, anastomosis, infections, and various other inflammatory conditions such as autoimmune disease. Malignant strictures, on the other hand, may arise from a primary airway neoplasm, invasion of airway by adjacent tumors, and metastatic tracheobronchial implants. Tracheobronchial stenosis, regardless of etiology, can have an extremely negative impact on a patient's quality of life and often presents significant and challenging problems for both the patient and the managing physicians. Multiple modalities of treatment have been used with varying degrees of success to treat airway stenosis including laser ablation, contact cryotherapy, electrocautery, argon plasma coagulation, photodynamic therapy, balloon dilation, stenting, and surgical resection.1–3
Spray cryotherapy (SCT) is the application of liquid nitrogen in a noncontact form. The therapy has gained acceptance in treating esophageal disease including Barrett esophagus.4–6 Early studies also showed promise in treating bronchial disease when used as an adjunct during bronchoscopy.7,8 The primary objective of this study was to assess the efficacy of bronchoscopic SCT in the treatment of benign and malignant airway stenosis. The secondary objective was to evaluate the safety of this treatment.
MATERIALS AND METHODS
This study is a single-institution, single-surgeon retrospective review of prospectively collected data on 22 patients who underwent SCT to re-establish airway patency from June 1, 2013 to May 1, 2014. The study was approved by the institutional review board at Temple University. Inclusion criteria consisted of all patients with airway stenosis secondary to both malignant and benign stenosis who underwent bronchoscopic SCT during the study period. Twenty-two patients met the study criteria. De-identified patients' demographics and treatment data were collected. Treatment strategy involved an initial bronchoscopy for evaluation of the lesion and SCT. During the initial evaluation, the need for follow-up bronchoscopy and need for further future therapy were determined. Complications were graded based on the Clavien classification.9
At initial bronchoscopy, luminal size in millimeters and percent of airway stenosis were estimated by a single physician observer. The degree of stenosis was then divided into grades based on the following classification, originally described by Finley et al: 1, ≤25%; 2, 26% to 50%; 3, 51% to 75%; and 4, ≥76%.7 The patients were also classified into benign and malignant groups for data analysis. We defined successful completion of treatment as a final patency of stenosis grade 1.
At the end of each procedure, visual bronchoscopic assessment was used to determine the grade of stenosis and the need for another future procedure. Once a final acceptable result was determined, patients were followed clinically.
The truFreeze System spray cryotherapy (CSA Medical, Inc, Baltimore, MD USA) was used to apply spray liquid nitrogen with a catheter that is passed into a therapeutic bronchoscope (Fig. 1). The procedure is done under general anesthesia with a large bore endotracheal tube (≥8 mm) or rigid bronchoscope. The spray is applied in intervals of 5 seconds, timed from onset of visible mucosal frost formation reaching 50% of the target area. Complete thawing of at least 30 seconds is allowed between each application. The number of cycles of spray and thawing is based on disease burden and response. Usually, 4 cycles are administered followed by dilation and/or debridement and finally 2 cycles. All patients underwent an additional procedure during bronchoscopy at the time of SCT including balloon dilation, stent placement, and/or mechanical debridement.
Ensuring adequate venting of the excess nitrogen gas to prevent barotrauma is essential during the procedure. Our protocol to accomplish this is by the following:
- Deflating the endotracheal tube cuff
- Disconnecting the tube from the ventilator circuit
- Visualizing adequate passive egress (misting) of gas through the endotracheal tube or rigid bronchoscope
- Confirming the absence of chest wall rise during the sprays
- Closely monitoring the heart rate, blood pressure, oxygenation, and EKG tracings
- Avoiding CST in lesions distal to the bronchus intermedius or left mainstem bronchus
- Avoiding CST in lesions that are associated with airway perforation
- When treating multiple ipsilateral lesions, treating first the proximal stenosis to facilitate venting when treating the distal one.
If at any time there is concern that passive venting is compromised, SCT is immediately aborted and the bronchoscope is immediately removed.
Data Analysis and Statistical Considerations
The baseline demographics, disease characteristics, treatment variables, and study end points were reported using descriptive summary statistics such as mean, median, and standard deviation for a continuous variable (eg, age and change in grade of stenosis posttreatment) and frequency and percentage for a categorical variable (eg, sex, pretreatment and posttreatment grades of stenosis, and comorbidities). Comparisons of continuous variables such as change in grade of stenosis posttreatment between the benign and malignant groups were performed using the Wilcoxon rank sum test owing to the relatively small group sizes as well as the fact that the standard t test assumptions were often violated (eg, the normality and/or homoscedasticity assumption did not hold). A χ2 test or Fisher exact test was used for comparisons of a categorical variable between the 2 groups, whichever is appropriate. Multiple comparison adjustments were not made owing to the exploratory nature of this study. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Inc, Cary, NC USA). P < 0.05 was considered statistically significant.
On these 22 patients, 66 bronchoscopies were performed for a total of 87 lesion treatments. The median number of lesions per patient was 1 (range, 1–2). The median age was 61.5 years (range, 28–75 years). Male patients accounted for 63.6% of the treatment group, and 36.4% were women. Causes of airway stenosis were benign in 45.5% (10 patients) and malignant in 54.5% (12 patients). The etiologies of malignant strictures were primary lung cancer (91.7% ) and invasion of airway by esophageal cancer (8.3% ). The location of malignant stricture was in the mainstem bronchus in 10 patients (83.3%), trachea in 1 patient (8.3%), and segmental bronchi in 1 patient (8.3%). The etiology of benign stricture was posttransplant anastomosis (90% ) and postintubation (10% ). The location of stricture was in the mainstem bronchus in 9 patients (90%) and trachea in 1 patient (10%). Eight patients (36.4%), mostly in the benign group (7/8), had undergone prior bronchoscopic treatments including stenting, dilation, and laser ablation.
Both groups were similar in age, largely male, and had similar rates of chronic lung disease (Table 1). The malignant group had a higher pack-year smoking history (median, 39 vs 20), fewer previous non-SCT bronchoscopies (30% vs 92%), and were slightly older (67% vs 40% older than 60 years old) compared with the benign group.
As shown in Table 2, at initial bronchoscopic evaluation, the median grade of stenosis was 4 for malignant disease and 3.5 for benign disease. The median final posttreatment grade of stenosis was 2 for malignant disease and 1 for benign. The median improvement in grade of stenosis after treatment was 2 grades for both the malignant and benign groups (Wilcoxon test, P = 0.92).
Successful treatment was defined as a final patency of grade 1 and was achieved in 42% of patients in the malignant group and 80% of the benign group (Table 3, Fig. 2). At the lesion level, 16 of the 27 lesions treated reached grade 1 (59.2%). Overall, 86.4% of patients had an improvement in at least 1 grade of stenosis after treatment. Two or more treatments were given in 70% of benign stenoses and 33.3% of malignant ones. Factors that were associated with a trend toward a higher successful completion rate (Table 4) include age older than 60, having undergone 2 or more SCT treatments, BMI less than 30 kg/m2, female sex, nonsmoker status, diabetes, benign disease, one or more prior non-SCT bronchoscopies, and post–lung transplant, although none of these associations reached statistical significance.
Additional treatments in our series included debridement, balloon dilation, and stenting. Debridement was performed for ablated tumor or granulation tissue. Balloon dilation was used for strictures that had a mural component and were not amenable to simple intraluminal debridement. When a stricture showed collapsibility after dilation, a temporary covered stent was used. In our series of 66 bronchoscopies, we performed balloon dilation 39 times (59%), debridement 26 times (39.4%), and both balloon dilation and debridement together in 10 of these treatments (15%). A stent was necessary only 4 times (6%).
The median follow-up from last SCT treatment in the malignant group was 13 (range, 0–212) days and 299 (range, 27–422) days for the benign group (Wilcoxon P < 0.001). There were no intraoperative deaths. In the benign group, there was one death (10%) within 30 days. This mortality was a patient status after lung transplant with a lengthy complicated hospital course that underwent SCT after more than 3 months of hospitalization. He succumbed to chronic respiratory failure secondary to severe deconditioning and ventilator-dependent pulmonary disease. Thirty-day mortality in the malignant group was 50% (6 patients; P = 0.06 compared to the benign group), with all deaths related to progression of disease. In the malignant group, 3 patients died from disease-related respiratory failure, and 3 patients died in hospice care. Ninety-day mortality for the benign group was unchanged from 30 days at 10% (1 patient), and 90-day mortality for the malignant group increased to 66.7% (8 patients) (P = 0.008).
The rate of procedure-related morbidity was 1.5% (1/66) or 4.5% of all patients (1/22). A patient who was treated for a lung transplant anastomotic stenosis had a preexisting small identifiable dehiscence of his bronchial anastomosis 7 months after transplantation. He required reintubation in the operating room, and was noted to have pulmonary edema and a clinically insignificant pneumomediastinum and pneumothorax on chest x-ray. He was successfully treated and was under observation.
These patients were followed clinically after completion of their treatments. During the time period of our study, there were no recurrences requiring additional bronchoscopic therapy.
Liquid nitrogen has a boiling point of −195.8°C and upon contact with tissue causes an almost immediate flash freezing of intracellular water resulting in coagulation necrosis and cellular death. Previous studies have shown that this effect is specific to cells and that there is a minimal effect on the surrounding collagen and extracellular matrix, which remains relatively undamaged.10,11 Theoretically, this may allow the preservation of a scaffold for recellularization and remodeling of tissue.12,13 It may also allow regeneration with minimal fibrosis and therefore minimal restenosis.14,15 The effect on benign strictures, which are mostly acellular, is less clear. One theory is that cryotherapy may cause “remodeling” of the connective tissue matrix to become more malleable, allowing easier and more atraumatic dilation of the stricture.8,14,15 When applied to benign strictures, the scar becomes softer and easier to stretch during balloon dilation without causing the commonly encountered fissuring and lacerations that may induce further fibrosis and stenosis.3 More research into the effect of SCT on the molecular structure of connective tissue is required to explain this finding. In comparison to SCT, all other thermal and mechanical ablative modalities have a tendency to induce a fibrotic response owing to the indiscriminate effect on both the epithelium and the connective tissue matrix. This can cause a recurrence or worsening of the stricture. However, SCT is usually not effective as a single modality and generally needs an adjunctive mechanical procedure to achieve patency. Such procedures include debridement, balloon dilation, and stenting.
Spray cryotherapy has been described in numerous reports to be an excellent option for endoscopic ablation of premalignant and malignant esophageal conditions.4,6,13,16–18 In the esophagus, it has been shown to destroy lesions down to a safe depth and to allow the regrowth of normal tissue in the treated areas.17,19 With regard to airway disorders, there are far fewer studies, but SCT has also been shown to have promising results in opening airways obstructed by malignant tumors.7,12,20–22 An earlier study in benign airway disease has also shown significant improvement in these types of strictures.8,23
Upon release into the warm airway, there is immediate expansion of the volume of nitrogen from the liquid to the gaseous form at a ratio of 1:645. Despite the relative simplicity of this procedure, there are therefore inherent risks, mainly those of unrecognized barotrauma. These risks include pneumothorax, pneumomediastinum, and nitrogen gas embolism. These risks, although rare, can be serious and fatal. It is therefore compulsory to follow the recommended venting protocol mentioned previously.
There are certain practical benefits to this modality in the airway compared to other forms of bronchoscopic ablative therapy. These include the ability to perform as an outpatient bronchoscopic treatment, the lack of procedure-related pain, and the ability to use the therapy while administering oxygen, since there is no combustion risk. The treatment is minimally invasive and has both hemostatic and analgesic effects. In addition, it is a relatively affordable modality compared to other treatments such as laser and photodynamic therapy. For these reasons, we embarked on this study to investigate the role of bronchoscopic SCT using the newer adjustable flow device (Fig. 1)22 as an adjunct in treating airway disease.
Our results provide evidence that SCT is equally efficacious for both benign and malignant types of airway stenosis, with an overall improvement of approximately 2 grades of stenosis with treatment. Patients with benign disease required more treatments to achieve completion. This significant difference in number of treatments is likely due to the structural difference in the mechanism of airway narrowing between benign and malignant disease. Most of the malignant group of patients had metastatic advanced-stage cancer and thus had higher mortality rates mostly from progression of disease.
In comparison to the work of Fernando and Finley, this series shows lower complication rates as experience with the technique grows and due to the technical improvements in the device itself. The review by Finley et al7 demonstrated a 19.3% complication rate in patients treated for malignant stenosis including 2 intraoperative deaths. This series had no morbidity and no intraoperative deaths in the malignant group. In the review by Fernando et al8 of treatment of benign stenosis, a 5.7% complication rate was reported with no mortalities. These results are comparable to the benign group in this study with a 4.5% morbidity rate. These results support the safety of SCT in both benign and malignant disease. Most patients in the benign group had post–lung transplant anastomotic strictures. This is a new area of study not previously examined in the literature.
Based on our results, a defined perforation or dehiscence of the airway is a contraindication to SCT, as evidenced by the complication noted on the single patient with dehiscence in our study. In addition, strictures distal to the bronchus intermedius or left mainstem bronchus, and inability to undergo general anesthesia would constitute other contraindications. Our approach is to treat multiple lesions during the same procedure. If more than 1 lesion exists ipsilaterally, we treat the proximal stenosis first to facilitate venting of nitrogen while treating the more distal one.
The limitations of the study include the retrospective nature, lack of a control group, and the small sample size. Additionally, the durability of the treatment was not assessed by long-term follow-up. Grading of airway stenosis was subjective based on bronchoscopic inspection. Lastly, SCT is typically used as an adjunct with other modalities, making it difficult to control for other potential confounding effects.
Despite these limitations, it has several strengths. It is the first study to show and compare the effect of SCT on benign and malignant airway lesions. It also sheds light on the role of SCT on posttransplant bronchial stenosis, which formed most of our benign stenosis group. Our study shows that SCT is a safe and effective method for achieving airway patency in a minimally invasive fashion. This study contributes to the small but growing body of literature supporting the use of SCT in benign and malignant airway disorders. Randomized controlled studies comparing SCT to different endoscopic modalities of treatment will improve our understanding of this therapy. In addition, more research is necessary to fully understand the effect of SCT on the the molecular and cellular structure of tissues.
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Obstruction of the airway is often a life-threatening emergency.Whether benign or malignant, there are amultitude of methods to treat this problem: photodynamic therapy, brachytherapy, stents, dilations, and spray cryotherapy with liquid nitrogen. No one method is without its potential complications. Janke and the group from Temple University demonstrate the usefulness of spray cryotherapy to help improve airway patency with minimal complications. This article supports the need for institutions to expand the use of spray cryotherapy as part of their armamentarium to relieve airway stenosis.