Physical Examination, Complementary Tests, and Functional Status Assessment

This patient presented with new exophytic endoluminal tracheal obstruction after stent placement, most likely consistent with hyperplastic granulation tissue formation, a benign form of central airway obstruction.¹ The main differential diagnosis of granulation tissue in patients with indwelling airway stents is tumor overgrowth, although mucus plugging and bacterial colonization can also cause firm, necrotic-appearing obstructive lesions. The exact prevalence of stent obstruction by granulation tissue versus tumor overgrowth is somewhat confounded by the fact that studies tend to report these events together rather than separately. With this caveat, the estimated frequency of recurrent obstruction from granulation tissue or tumor is 9% to 67% in patients with metal stents, and 6% to 15% in patients with silicone stents.² Tumor overgrowth tends to occur when only the tumor area is covered and no cancer therapy is offered; it is most often seen in patients with partially covered indwelling metal stents because malignant tissue grows through exposed wire mesh, causing obstruction (Figure 3-3). Our patient, however, had no history of cancer; his stent was placed for a benign post intubation stricture, and the rapid onset of exophytic tissue growth was not consistent with a malignant tumor growth rate.

Figure 3-3 A, Partially covered 14 × 40 mm Ultraflex stent placed in the left main bronchus in a patient with extrinsic compression and mucosal infiltration from primary lung adenocarcinoma. B, Circumferential tumor growth through the uncovered portion of the stent was seen on follow-up bronchoscopy performed 3 weeks later.

Granulation tissue formation is less predictable. It seems that patients with known keloids or chronic airway infection are at higher risk.³ Oversizing the stent has been suspected as a risk factor, especially when stents are placed in the upper trachea or subglottis (see video on ExpertConsult.com) (Video I.3.1). For silicone, as well as metal, friction between the sharp edges of the stent and the airway mucosa may cause granulation tissue formation. In addition, when electrocautery is used, the direct (aka galvanic) currents generated* around the metal wires may be cofactors in granulation tissue formation.⁴ Shearing forces at the stent-mucosa interface created by differential motion of the stent relative to the airway contribute to constant stimulation of airway mucosa, further leading to reactive granulation tissue formation. Hyperplastic granulation tissue formation can be seen at the site of a lung transplant surgical anastomosis^†5,6 or at the anastomosis site after tracheal sleeve resection for tracheal stenosis (Figure 3-4). One study showed that 31% of patients with a lung transplant or benign disease developed granulation tissue after placement of a self-expandable metallic stent.⁵

Figure 3-4 A, Patient with severe web-like tracheal stenosis underwent tracheal sleeve resection, (B) resulting in improved airway patency. C, Several weeks later, however, severe dyspnea triggered a flexible bronchoscopy, which revealed a large amount of obstruction granulation tissue at the anastomotic site. D, This tissue was very friable and bled easily just by gentle touch with the flexible bronchoscope.

Silicone stent insertion performed using rigid bronchoscopy under general anesthesia was considered an acceptable alternative to surgery for our inoperable patient with complex stenosis.* In fact, silicone stents provide long-term airway patency in nonsurgical candidates with a variety of central airway obstructive lesions.^†7–9 Stent-related complications, however, are not uncommon and in one series included migration (17.5%), obstruction from secretions (6.3%), and significant granulation tissue formation at the proximal or distal extremities of the stent (6.3%).¹⁰ This latter complication may promote the development of secondary stenosis.⁵ It is likely that other complications of stent insertion, such as kinking, fracture, or compression of mucosal vasculature due to excessive centrifugal force exerted by expanding or self-expanding stents, also contribute to granulation tissue formation. As in our patient, diagnostic flexible bronchoscopy should always be performed when a stent-related adverse event is expected. This will confirm or rule out problems such as mucus plugging or stent migration and will allow an accurate reassessment of the stenosis, the degree of mucosal inflammation, associated cartilaginous collapse, and the relative amount and location of hypertrophic fibrotic tissue.¹¹ Bronchoscopy is the current standard for the detection and treatment of stent-related complications; in nonurgent situations, it usually involves a two-step procedure. Initially, diagnostic flexible bronchoscopy is performed to detect and characterize a stent complication; if a treatable complication is detected, rigid bronchoscopy may be required for therapeutic intervention. In our case, a large amount of obstructing granulation tissue was found proximal to the stent during flexible bronchoscopy* (see Figure 3-1).

This patient had developed significant granulation 2 months after stent placement, probably as a result of abnormal wound healing—a process that eventually led to hypertrophic fibrotic tissue formation and circumferential stenosis. The exact duration of indwelling stent placement necessary to cause airway injury and granulation is not known, and the exact molecular mechanisms responsible for this are only partially understood.^† Some of the better studied mechanisms include overexpression of profibrotic transforming growth factor (TGF)-β₁ in the extracellular matrix¹² and the presence of high levels of vascular endothelial growth factor (VEGF) expression in the submucosal layers.¹³ Wound healing also depends on local and systemic factors, such as infection, pressure, tissue necrosis, age, and comorbidities.¹⁴ In this regard, patients with malignant disease develop less stent-related granulation tissue formation (≈4%)—a phenomenon that can be explained in part by the use of radiotherapy and chemotherapy, leading to a less pronounced inflammatory response to the presence of the stent.⁵

Comorbidities

This patient suffered from several cardiovascular comorbidities. An assessment of risk for myocardial infarction or death and methods to reduce or eliminate these risks should be addressed before surgery is performed on such patients under general anesthesia.¹⁵ Perioperative myocardial infarction causes substantial morbidity and prolonged hospitalization; mortality rates as high as 25% to 40% are associated. Noninvasive stress testing is widely used to help predict risk of perioperative complications, but the poor predictive power of these tests limits their usefulness. No data suggest benefits of percutaneous coronary intervention or CABG in reducing noncardiac surgical risk. In addition, angioplasty with stenting and its need for anticoagulation can expose patients to increased risk of perioperative bleeding. In general, stable patients who have previously undergone coronary revascularization may safely undergo surgery, especially low cardiac risk procedures such as bronchoscopic interventions. In one study of patients who had undergone high-risk noncardiac surgeries, the revascularized patients experienced significantly fewer cardiac complications perioperatively when compared with patients without previous CABG.¹⁶ It is currently recommended that asymptomatic patients who have undergone CABG in the previous 5 years should proceed directly to noncardiac surgery without further preoperative evaluation.¹⁷ From a purely cardiac standpoint, our patient had no contraindication to rigid bronchoscopy under general anesthesia, making it a possible alternative for granulation tissue removal.

Postoperative pulmonary complications are at least equally prevalent and contribute similarly or more to morbidity, mortality, and length of stay in patients undergoing noncardiac surgery.¹⁸ With regard to perioperative pulmonary risk stratification, patient-related risk factors for postoperative pulmonary complications* include advanced age,^† American Society of Anesthesiologists class 2 or higher, functional dependence, COPD, and congestive heart failure (all were seen in our patient). Abnormal findings on chest examination (defined as decreased breath sounds, prolonged expiration, rales, wheezes, or rhonchi) were the strongest predictors of postoperative pulmonary complication rates (odds ratio, 5.8).¹⁸ Evidence supports procedure-related risk factors for postoperative pulmonary complications, including general anesthesia and prolonged surgery (2.5 to 4 hours). The major procedure-related risk factors (vascular, abdominal, or thoracic surgery) confer higher risk for pulmonary complications than is associated with patient-related risk factors.¹⁸ From a pulmonary standpoint, our patient was not an optimal candidate for general anesthesia, and granulation tissue was therefore removed using the flexible bronchoscope and moderate sedation.

Support System

This patient with advanced lung disease and his partner had to cope with a life limited by constant dyspnea. Although dyspnea may vary in severity from day to day, it invariably affects how patients and their partners see themselves and their place in society; people develop a feeling of isolation, helplessness, and fear.¹⁹ Indeed, results of studies show that family caregivers voiced their feelings of helplessness and their sense of relief and security once they had decided to seek help (e.g., when the patient was admitted for acute care).¹⁹ Interventions that target the family setting in which chronic disease management takes place have thus emerged as an alternative to traditional strategies that focus only on individual patients, or that consider family only as a peripheral source of positive or negative social support. When this approach is used, the educational, relational, and personal needs of all family members are emphasized with the aim of improving the quality of relationships among family members with respect to the disease.²⁰

Patient Preferences and Expectations

During our preprocedure interview, our patient expressed his wish to avoid general anesthesia if possible. He was informed of available therapeutic options for his current airway problem, such as flexible bronchoscopy removal using laser, electrocautery, argon plasma coagulation, cryotherapy, or rigid bronchoscopy with stent revision, and removal of tissues by rigid bronchoscopic resection, laser, or electrosurgery. After he had been informed of the risks and benefits of available therapeutic alternatives for his situation, he elected to undergo flexible bronchoscopy with electrosurgery to improve symptoms acutely so that he could avoid rigid bronchoscopy.

Indications

The obstructing granulation tissue resulted in stridor and respiratory distress at rest. The bronchoscopic procedure was indicated in an attempt to restore airway lumen patency and to improve airflow and symptoms.

Contraindications

This patient had no absolute contraindications to flexible bronchoscopy. In fact, the only contraindication to elective bronchoscopy is refractory hypoxemia.* Although hypoxemia is associated with cardiac arrhythmias in 11% to 40% of patients who undergo fiberoptic bronchoscopy, cardiac rhythm disturbances are rarely clinically important. The American Thoracic Society recommends avoiding bronchoscopy and bronchoalveolar lavage in patients with hypoxemia that cannot be corrected to at least a partial pressure of arterial oxygen (PaO₂) of 75 mm Hg or to a saturated oxygen level in hemoglobin (SaO₂) greater than 90% with supplemental oxygen. In case of use of electrosurgery, any high amount of supplemental fraction of inspired oxygen (FiO₂) would pose a risk for airway fire and stent ignition. Our patient was on 3 L of oxygen at baseline, which is the equivalent of an FiO₂ of 0.32.*

Expected Results

Electrocautery uses high-frequency current, which leads to thermal tissue destruction. This bronchoscopic modality has been used successfully to remove granulation tissue ²¹ and can be performed using flexible or rigid bronchoscopy; when the rigid scope is used, the electrode tip must not be in contact with the rigid tube or other instruments or devices (e.g., forceps, stent) to avoid formation of an electrical circuit with the equipment or the operator (Figure 3-5). The main advantage of electrocautery over other techniques (photodynamic therapy, brachytherapy, or cryotherapy) is its rapid results. Care should be taken to avoid damaging normal airway wall structures or the indwelling airway stent. Necrosis caused by electrocautery depends on the voltage difference between the probe and the tissue, the surface area of contact, the duration energy is applied,^† and the presence of blood or mucus.²² For instance, in one study, superficial tissue damage was caused despite short duration of bronchoscopic electrocautery using 30 W power, use of a flexible electrocautery probe (2 mm² surface area) for less than 2 seconds. A longer duration of coagulation (3 or 5 seconds) caused damage to the underlying cartilage.²²

Figure 3-5 A, The rigid electrocautery probe is placed directly onto the granulation tissue formed distal to the stent, (B) once coagulated tissue is removed using the rigid forceps; despite minimal use of electrocautery (25 W, 3 second pulses) and lack of direct contact with the stent, collateral thermal stent damage characterized as a spontaneous break in the continuity of the silicone layer inside the stent was evident (black arrows).

Team Experience

The operating physician is responsible for settings, dosing of energy, and any decision regarding use of the electrosurgical unit. Although all staff members present should understand and confirm the settings used, the physician determines what modes, settings, and duration of delivery are used.

Therapeutic Alternatives to Granulation Tissue Removal

The choice of treatment modality is based on knowledge of its tissue effects, availability, operator experience, safety (e.g., electrocautery may not be possible in a patient who requires substantial supplemental oxygen to maintain oxygen saturation), and costs. Alternatives to granulation tissue removal include systemic and bronchoscopic therapies such as laser, electrocautery, argon plasma coagulation (APC), cryotherapy or rigid bronchoscopy with stent revision, and removal of tissues using rigid bronchoscopic forceps.

1. Medical therapy: Because wound healing is the source of the problem, researchers have tried to modulate and suppress this process.¹³ Several agents have been tested for controlling the wound-healing process in airway stenosis: (1) inflammation phase: antibiotics, steroids, and hyperbaric oxygen (HBO)*; (2) proliferative phase: antibiotics, steroids, mitomycin,^† 5-fluorouracil (5-FU)^‡/triamcinolone, HBO; (3) maturation phase: halofuginone,^§ beta-aminopropionitrile , colchicine, penicillamine,^‖ and N-acetyl-l-cysteine (NAC).^¶ Most of these agents were investigated in animal models. Three modalities were more thoroughly investigated: steroids and antibiotics, mitomycin, and antireflux medications.¹³ Treatment with steroids and antibiotics did not have consistent results in different animal and human studies. Most studies demonstrated the superiority of mitomycin when compared with placebo if used immediately after tissue injury (i.e., on fresh, inflamed scar, containing mostly granulation tissue). Most of these studies show a tendency toward a favorable effect of mitomycin, yet results from the only prospective double-blind, randomized human study performed as of this writing did not demonstrate improvement when topical mitomycin was applied.¹³ Reflux prevention includes education and behavioral changes, along with drugs such as proton pump inhibitors, H₂-receptor antagonists, and prokinetic agents.¹³ Because of limited data supporting its efficacy and the severe nature of symptoms and the degree of obstruction, simple medical therapy was not offered to our patient.

2. Neodymium-doped yttrium aluminum garnet (Nd:YAG) laser: Effect is based on thermal tissue destruction resulting from light-tissue interaction. The distribution of energy depends on the optical properties of the material and the wavelength characteristic of the laser light. As absorbed energy is converted into heat, a rise in the temperature of the target tissue or material occurs; the temperature will rise above threshold levels only if the absorbed power density exceeds the capacity of the material to conduct heat away from the impact site. For example, at low power densities, the poor absorption of the Nd:YAG laser and its pronounced scattering result in slow homogeneous heating of a large volume of tissue without serious mechanical damage to the tissue surface.²³ At high power densities, however, the temperature 2 to 3 mm below the tissue surface rises rapidly, prompting vaporization of water content and a pocket of steam with pressure high enough to rupture overlying tissues.²⁴ Certain quantities of laser energy, defined by power density, would cause local heating without the extreme temperature elevation required to disrupt stent integrity or prompt stent ignition.² In these circumstances, laser-induced stent damage* may cause substantial morbidity from airway burn injury in case of stent ignition, or airway wall and vascular perforation in case of metal stent rupture. To identify margins of safety within which bronchoscopic Nd:YAG laser resection can be performed without damaging indwelling airway stents, an experimental in vitro study simulating a patient-care environment was conducted^† using Nd:YAG laser performed at FiO₂ of 0.4 using fiber-to-target distances of 10 mm and 20 mm, and noncontact, continuous-mode, 1 second pulses at power settings of 10 W, 30 W, and 40 W. Results of this study showed that uncovered Wallstent and silicone stents were not damaged when Nd:YAG laser energy was delivered using power densities less than 172 W/cm² (10 W, 10 mm), but were damaged at power densities greater than 225 W/cm² (30 W, 20 mm); uncovered Wallstents, covered Wallstents, and silicone stents all were damaged at power densities greater than 225 W/cm² and at power settings greater than 30 W; covered Wallstents, however, had a high likelihood of ignition at all power densities studied (75 W/cm², 172 W/cm², 225 W/cm², 300 W/cm², 518 W/cm², and 690 W/cm²).^‡2,25 In fact, in another experimental study, investigators found that metal stents were destroyed after just one 25 W pulse delivered 4 mm from the target, prompting authors to conclude that the Nd:YAG laser should not be used in patients with indwelling Wallstent, Strecker, and Palmaz metal stents²⁶ for fear of stent fracture. The importance of coexisting mucus or blood in the setting of indwelling airway stents was also well demonstrated in an in vitro study, in which investigators were able to ignite blood- or soot-covered silicone stents using multiple laser power settings. Clean silicone stents could not be ignited regardless of power density or oxygen concentration.²⁷

3. Argon plasma coagulation (APC): This procedure is based on argon gas ionization by current, which will lead to thermal tissue destruction. Typically indicated for hemoptysis and malignant exophytic endoluminal obstruction,²⁸ APC has been used successfully for treating granulation tissue.²⁹ Because argon plasma is electrically conductive, an electrical spark jumps from the tip of the electrode to the target tissue, creating a thermal effect. The probe should not touch the tissue surface at any time (Figure 3-6); the distance between the probe’s distal tip and conductive biologic tissue must be approximately 5 mm or less, and the target tissue must be conductive. Tissue that is dehydrated, carbonized, or denatured will resist the flow of electrical current. In a large prospective study of 364 patients treated over a 4-year period, authors showed that APC is effective and safe in treating a variety of central airway disorders, including stent obstruction by tumor or granulation tissue (overall 67% success rate) with a complication rate of 3.7%.³⁰ In a small case series of three patients who developed strictures and stent-related granulation tissue after solid organ transplantation, the success rate of APC was 100% with no complications.³¹ When this technique is used, however, a concern is that gas forced into the airway wall may collect within a blood vessel, causing gas embolism. Argon gas is heavy, inert, and 17 times less soluble in the body than carbon dioxide, and it may pass into the systemic circulation. Both cerebral gas embolism and cardiac arrest have been reported after airway applications of APC.^32,33

Figure 3-6 A, Argon plasma coagulation (APC) probe is seen in near contact mode with granulation tissue during flexible bronchoscopy in vivo. B, Damaged silicone stent after APC application at fraction of inspired oxygen (FiO₂) of 1.00. C, Melted Ultraflex stent membrane is noted after APC application. D, Broken stainless steel uncovered Wallstent wires can cause adjacent tissue damage through their conducting capabilities (note the charred tissue).

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