Subglottic Stenosis

Etiology

Subglottic stenosis can result from either congenital or acquired etiologies. In cases of congenital subglottic stenosis, there is no history of trauma or airway manipulation, such as endotracheal intubation. During normal embryonic development, the laryngeal lumen typically undergoes recanalization in the third month of gestation after the completion of epithelial fusion. However, in congenital stenosis cases, this recanalization process fails to occur.

Additional potential causes include burns, ingestions, radiation exposure, infections, and inflammation stemming from gastroesophageal reflux disease (GERD). Additional triggers include autoimmune disorders such as granulomatosis with polyangiitis, amyloidosis, systemic lupus erythematosus, sarcoidosis, rheumatoid arthritis, relapsing polychondritis, or IgG4-related disease. Congenital subglottic stenosis may also be associated with trisomy 21, CHARGE, and 22q11 deletion syndromes. Furthermore, Pallister-Killian syndrome, a rare genetic disorder characterized by tetrasomy 12p mosaicism, can manifest with multisystem defects affecting the respiratory system and progressive subglottic stenosis.[3] 

Acquired subglottic stenosis is more prevalent than congenital stenosis and is primarily iatrogenic, frequently arising from prolonged intubation. Historically, acquired subglottic stenosis in children has been caused by prolonged intubation lasting longer than 12 to 24 hours for 90% of cases.[4][5] 

Although advancements in medical care in the 1960s and 1970s reduced mortality rates for various conditions, they also extended intubation periods, consequently emerging as a significant risk factor for acquired subglottic stenosis. The tracheal mucosa maintains a capillary perfusion pressure of approximately 30 mmHg. Inflating a cuffed endotracheal tube balloon above this pressure can lead to vascular compromise in as little as 15 minutes.[6] This can lead to tissue necrosis, followed by an inflammatory response marked by fibroblast deposition and heightened collagen production, resulting in tissue thickening and airway stenosis. 

Many healthcare professionals conducting intubations have access to a cuff pressure manometer. However, patients are at potential risk of permanent tissue injury if cuff pressure is not routinely checked and appropriate levels are confirmed after intubation. Even when the tube cuff is not excessively inflated, prolonged intubation may cause tissue injury through direct pressure or shearing forces, potentially leading to subglottic stenosis. Additional causes of acquired subglottic stenosis encompass external trauma, such as motor vehicle accidents, or injuries from objects, such as clotheslines. These incidents can result in tissue injury, necrosis, and inflammation in the subglottis, ultimately leading to stenosis through a mechanism similar to that observed in endotracheal intubation.

The age-based Cole formula was used to estimate the appropriate endotracheal tube size for a specific patient in the past, which was calculated as (age/4) + 4.[7] However, further analysis demonstrated that this formula accurately determines the correct endotracheal tube size in only 50% to 75% of cases, potentially subjecting patients to tissue injury from an excessively large tube.[8] 

Subsequent studies have demonstrated that the Duracher formula is the most accurate method for determining the appropriate endotracheal tube size, calculated as (age/4) + 3.5.[9] Nonetheless, other studies recommend the utilization of adjuncts, such as plain film or ultrasound, to determine the appropriate endotracheal tube size.[10] 

Additional factors that can increase the risk of postintubation subglottic stenosis include a respiratory infection within 14 days of intubation, multiple intubations, unplanned extubations, obesity, diabetes, and GERD.[11]

Epidemiology

In the early 20th century, before the advent of endotracheal intubation, the incidence of subglottic stenosis was relatively low, with congenital cases being the most predominant. However, introducing endotracheal tubes elevated the prevalence of acquired postintubation stenosis, surpassing congenital causes in stenosis rates by a considerable margin. After being extubated, more than 44% of pediatric intensive care unit patients experience postintubation stridor, whereas up to 57% of adult and pediatric patients exhibit evidence of postintubation acute laryngeal injury. The incidence of stenosis is comparatively lower, ranging from 0.3% to 11.38%.[8][12] 

Idiopathic subglottic stenosis is most prevalent among Caucasian women during their perimenopausal period. This condition is believed to be associated with factors such as reflux, upregulation of estrogen in subglottic mucosa, or autoimmune response.[13] A comprehensive understanding of these factors is essential for effectively managing and preventing this condition.

Pathophysiology

In cases of acquired subglottic stenosis, the endotracheal tube exerts pressure that induces tissue necrosis at the point of contact, subsequently causing mucosal edema and ulceration. This event disrupts normal ciliary flow, resulting in mucociliary dysfunction, which can eventually increase susceptibility to infections. The subsequent inflammatory response stimulates the proliferation of granulation tissue and the recruitment of fibroblasts to the affected area, ultimately resulting in tissue thickening and airway stenosis.[1] Primary healing is hindered due to the mobility and loose characteristics of the subglottic submucosa, as well as the inadequate vascularization of the cartilage.

For idiopathic subglottic stenosis cases, the condition is frequently found at the cricoid cartilage, with the narrowest point between the cartilage's upper edge and the first tracheal ring. Although this stenosis is often circumferential, it can occasionally exhibit an eccentric presentation.

Histopathology

Histologically, tissue ulceration is often observed after intubation, ranging from mild epithelial disruption to full-thickness injury. Not all cases of tissue ulceration result in stenosis.[14] In cases of deep or full-thickness tissue ulceration, exposed cartilage may trigger a foreign body reaction, resulting in the deposition of significant granulation tissue.

Histopathological findings of idiopathic subglottic stenosis typically exhibit dense fibrosis with a keloidal-like pattern and interspersed fibroblasts. Furthermore, replacing the frequently observed collagen type III with the stronger collagen type I is common in subglottic stenosis.[15] The overlying epithelium often exhibits metaplasia, whereas the cartilaginous rings generally remain relatively normal. Although estrogen may have a role in idiopathic subglottic stenosis, no observed overexpression of estrogen or progesterone receptors exists in the disease process.[16]

History and Physical

Individuals with suspected subglottic stenosis should undergo a comprehensive history and physical examination. Although there may not always be a history of recurrent croup or exertional stridor, it is essential to collect information regarding a history of intubation, respiratory illnesses, laryngeal trauma, syndromic diagnoses, craniofacial abnormalities, feeding status, and voice quality.[17] Furthermore, it is crucial to inquire about GERD symptoms, as it can cause irritation of the glottic and subglottic mucosa and exacerbate stenosis.

Stridor is the primary presenting symptom of stenosis, which may be biphasic, inspiratory, or expiratory, regardless of whether the stenosis is congenital or acquired. In cases of congenital subglottic stenosis, symptoms typically manifest shortly after birth and may include dyspnea, air hunger, and retractions in the suprasternal, intercostal, and diaphragmatic regions. An abnormal cry, aphonia, or hoarseness may occur if the stenosis affects the vocal cords.

Patients with acquired subglottic stenosis often have a history of laryngeal insult or intubation. Their symptoms may appear as early as 3 to 4 weeks after the initial insult or as late as several years later. Therefore, patients presenting with stridor need to undergo a comprehensive evaluation, which often involves a flexible laryngoscopy performed by an otolaryngologist to evaluate further potential causes. Although a physical examination by a primary care provider may not always reveal abnormal findings indicative of a diagnosis, flexible laryngoscopy can demonstrate narrowing of the subglottic tissue.

Evaluation

The primary method of diagnosing subglottic stenosis is through endoscopic examination using flexible fiberoptic laryngoscopy. This examination will offer an indirect visual assessment of the subglottis and can be conducted on patients of any age while awake within the otolaryngology clinic. Furthermore, this examination will provide insight into the dynamics of vocal cord function and tracheal patency. Rigid laryngoscopy and bronchoscopy are frequently performed in patients in the operating room under general anesthesia to achieve a clearer view of the subglottis and assess the degree of stenosis.

Spirometry is a valuable marker for monitoring patients with known subglottis stenosis. Parameters such as peak inspiratory flow rate (PIFR), peak expiratory flow rate (PEFR), and forced vital capacity (FVC) have been studied and found to be relatively predictive of the necessity for operative intervention.[18][19][20] 

Although imaging techniques do not typically have a significant role in diagnosing adult subglottic stenosis, they can be used to assess anatomical anomalies in patients with an unclear etiology for their stenosis. Computed tomography and magnetic resonance imaging modalities can be utilized to examine the stenotic segment and measure the length of the stenosis. However, this information may not always provide specific clinical utility.

Long-range optical coherence tomography (OCT) has been proposed as a diagnostic tool for neonatal subglottic stenosis.[21] OCT can effectively characterize changes in subglottic mucosa resulting from endotracheal intubation. However, OCT use is limited due to the lack of automated data analysis for image review, resulting in a significantly labor-intensive process to obtain results.

The Cotton-Myer grading system is predominantly utilized to evaluate subglottic stenosis. Grading requires an airway evaluation performed under general anesthesia. This evaluation involves comparing the diameter of the smallest available endotracheal tube that can pass through the subglottic lumen while tolerating normal leak pressures, typically in the range of 10 to 25 cm H₂O, to the outer diameter of the expected age-appropriate endotracheal tube size. This comparison enables the calculation of the percent obstruction.[22] 

The Cotton-Myer grading system is categorized as follows:

• Grade 1 stenosis: Lumen obstruction between 0% and 50%.
• Grade 2 stenosis: Lumen obstruction between 51% and 70%.
• Grade 3 stenosis: Lumen obstruction between 71% and 99%.
• Grade 4 stenosis: Complete lumen obstruction.

Treatment / Management

Subglottic stenosis management may encompass observation, injection therapies, or surgical procedures, including dilation, stent placement, laryngotracheal reconstruction (LTR), or tracheostomy. Observation with routine at-home or in-clinic spirometry may be a reasonable approach for patients with mild symptoms. Spirometry is a practical, noninvasive method for measuring upper airway obstruction, and it can provide helpful information regarding the necessity for surgery and postoperative stability.[23] If there is a significant decrease in flow rates or FVC, it is advisable to consider a more proactive management approach.

Serial intralesional steroid injection (SILSI) is a recognized minimally invasive treatment option that yields favorable long-term outcomes. Although Kenalog-40 injection is commonly used for managing subglottic stenosis, the dilution of the medication may vary based on the provider's preference and patient-specific factors, such as the degree of stenosis firmness. Steroid injections are typically administered every 3- to 4-week intervals for a series of 6 injections. Through this technique, 83% of patients undergoing SILSI avoid the need for additional surgical intervention.[24] Mechanistically, steroids transform the profibrotic stenotic area into an antifibrotic region, resulting in the softening of the stenosis and improvement in both subjective and objective airway parameters.

5-Fluorouracil (5-FU), a thymidylate synthase inhibitor, is used in specific locations for injecting subglottic stenosis. Recent data indicates that 5-FU may be more effective than steroids in reducing vocal fold scarring.[25] However, further research is necessary to explore the efficacy of 5-FU compared to steroids for treating subglottic stenosis. In addition, mitomycin C can also be administered via injection to reduce scarring in patients with subglottic stenosis. However, this treatment approach is not commonly utilized as the medication is associated with an increased risk of adverse effects due to its potent antitumor properties.

Patients requiring further intervention despite serial injections are often advised to undergo the initial operative procedure, which typically involves either the excision of the stenosis or dilation. Dilation can be performed through either a balloon or rigid dilation method, which may include radial incisions made with a knife or a carbon dioxide (CO₂) laser to aid in dilation and, if necessary, excision. Patients often require multiple dilation procedures, although the timing between procedures can generally be extended as a steady state is achieved.[26]

Balloon dilation may be considered a first-line treatment for acquired subglottic stenosis, with over 90% success rates in improving symptoms and reducing the need for additional surgical procedures.[27] However, several providers prefer to begin the treatment with injections before progressing to dilation procedures. The success rate of balloon dilation is closely associated with a shorter duration and a lower initial grade of stenosis, younger patient age, and the absence of tracheotomy.[28] (B2)

Patients who require frequent dilation intervals and wish to avoid the potential complications associated with open-airway surgery may opt for endoscopic laryngotracheoplasty, also known as the Maddern procedure. The Maddern procedure involves the complete resection of the subglottic mucosa, including the scar, while preserving the cartilaginous framework.[29] Although comprehensive long-term outcomes have not been extensively studied, this approach may provide another viable option for patients before considering open-airway surgery.(B3)

Mature and severe laryngeal stenosis that does not respond to endoscopic techniques, such as injection or dilation, may necessitate more extensive open-airway procedures. These procedures include LTR through either an anterior or posterior cricoid split, cricotracheal resection, or tracheostomy. For many patients with severe subglottic stenosis, a tracheostomy is often necessary, followed by open-airway procedures, to optimize the chances of successful decannulation. These reconstructive procedures can be performed either as single-stage or double-stage interventions.

Single-stage procedures do not involve tracheostomy during reconstruction, although patients may remain intubated for several days postoperatively until airway edema resolves. In contrast, double-stage procedures involve tracheostomy and airway stent placement during the initial reconstruction. Decannulation and removal of the airway stent occur during a second procedure conducted weeks to months after adequate healing. Indications for double-stage procedures include multilevel stenosis, severe craniofacial malformations, severe neurological or respiratory comorbidities, and salvage procedures.[30] 

Traditional management for infants born with subglottic stenosis includes tracheostomy and serial airway evaluations conducted every 3 months to determine the necessity and timing of airway reconstructive surgery. Anterior and posterior cricoid split procedures are suitable for mild-to-moderate subglottic stenosis and involve the placement of harvested costal cartilage to enlarge and maintain the patency of the stenotic airway. In anterior and posterior cricoid split procedures, the objective is to widen the cricoid ring by inserting a costal cartilage graft. In both techniques, a vertical anterior airway incision is made, which includes the cricoid, 1 to 2 tracheal rings, and the inferior aspect of the thyroid cartilage.

In the posterior cricoid split procedure, an additional incision is made through the posterior aspect of the cricoid cartilage. The cartilage graft is inserted into the airway through the anterior incision and is secured posteriorly, eliminating the need for posterior sutures. After positioning the cartilage graft, the anterior tracheal incision is closed with sutures. In the anterior cricoid split procedure, the cartilage is placed in the anterior gap created after incision and is sutured into place.

Based on the Cotton-Myer grading system, patients with subglottic stenosis grade 1 or 2 (≤70% lumen obstruction) can often be treated conservatively with observation and, in some cases, endoscopic procedures, although these are not definitive indications. Conversely, patients with grade 3 or 4 subglottic stenosis (>70% obstruction) on the Cotton-Myer grading system often necessitate more aggressive surgical intervention, which may include tracheostomy.[1]

Differential Diagnosis

Tracheal and laryngeal pathologies can be categorized into stenosis, infection, neoplasm, and aspiration.[31] Airway stenosis can stem from various causes, including subglottic and tracheal stenosis, vascular ring, aberrant innominate artery, and laryngeal web.[32] Subglottic and tracheal stenosis can occur due to prolonged intubation, surgical procedures, autoimmune or inflammatory disorders, infections, and GERD.[33] 

The differential diagnosis for subglottic stenosis includes both benign and malignant etiologies. Benign causes include posttraumatic sequelae, infections, rheumatic diseases, and benign tumors such as papillomas, hemangiomas, and granular cells. Malignant etiologies include squamous cell carcinoma, chondrosarcoma, and laryngeal lymphoma.[34]

Prognosis

The prognosis is generally favorable for most patients with subglottic stenosis, as they typically respond well to injections or endoscopic procedures. These interventions have low morbidity and do not pose significant adverse effects. Minimally invasive procedures are more likely to succeed when the initial stenosis is of a lower grade.[35] However, due to the relatively high recurrence rates, long-term surveillance is recommended for all patients with a history of subglottic stenosis.[36]

Complications

Complications of subglottic stenosis include progressive airway obstruction, elevating the risk of acute airway obstruction following laryngeal insult from acute infection, inflammatory conditions, or trauma. Restenosis occurs in up to 25% of patients, and all the surgical interventions mentioned carry some risk, including the potential loss of the airway. However, these procedures have been extensively studied and are considered safe when performed by experienced surgeons.

Complications following tracheostomy require special attention due to the associated risk of morbidity and mortality. Accidental decannulation can result in the sudden loss of the airway, leading to desaturation and fatal outcomes. In the initial period following tracheostomy, attempting to insert the tracheostomy tube through the stoma into the airway can inadvertently create a false tract. Failure to recognize this can result in massive crepitus when connecting to a ventilator, potentially leading to mediastinitis and fatal outcomes. Tracheostomy tube changes should be performed only by qualified personnel after allowing adequate time for the tract to mature.

Tracheoinnominate fistula is another dreaded complication of tracheostomy, often manifesting within 3 weeks of the procedure in 75% of cases.[37] Approximately 50% of patients with tracheoinnominate fistula exhibit a sentinel bleed before experiencing massive hemorrhage. Upon diagnosis, the tracheostomy balloon should be immediately overinflated, and a finger should be inserted through the neck incision to compress the innominate artery against the posterior sternum, a technique known as the Utley maneuver. The patient should then be promptly transferred to the operating room, where definitive repair will be performed by otolaryngology and possibly cardiothoracic surgery. Additional risks associated with tracheostomy include tracheoesophageal fistula and tracheocutaneous fistula, but these typically entail lower morbidity levels than the abovementioned complications.