Evaluation of Off‐Label Postoperative Inhaled Steroid Use in Tracheal and Cricotracheal Resection

Authors: Jason Shin Chwa, Alexander Tu Hong, Elizabeth Ann Shuman, Karla O'Dell

Abstract

Objective

Tracheal resection (TR) and cricotracheal resection (CTR) are associated with anastomotic complications. Off‐label use of inhaled corticosteroids has gained popularity for reducing tracheal granulation tissue, though adoption remains limited due to unclear safety and efficacy. This study used a national database to evaluate associations between postoperative inhaled steroid use and adverse effects, granulation tissue formation, and repeat surgical intervention.

Study Design

Retrospective cohort study.

Setting

Multicenter study using TriNetX, a federated electronic health records network.

Methods

Adult patients undergoing TR/CTR between March 2005 and March 2025 who received inhaled steroids (ciprofloxacin‐dexamethasone, dexamethasone, budesonide, fluticasone, mometasone, and beclomethasone) within 1 day postoperatively were included. Patients were excluded if they had diagnoses commonly requiring similar medications or received study agents within 1 month before surgery. Propensity score matching balanced covariates, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for outcomes at 30 days and 3 months. Outcomes included adverse safety events, granulation tissue formation, and repeat airway surgery.

Results

The matched cohort included 284 patients in each group. Inhaled steroid use was associated with decreased odds of adverse safety side effects, granulation formation, and repeat airway surgeries at both timepoints, though only repeat procedures at 30 days reached statistical significance (OR 0.60, 95% CI 0.42‐0.85).

Conclusion

Postoperative inhaled steroid use in TR/CTR patients demonstrated excellent safety with no increased adverse events and was associated with a significant 40% reduction in the incidence of repeat surgeries within 30 days. Further studies should assess potential clinical benefits more definitively.

Laryngotracheal stenosis, characterized by abnormal narrowing of the airway, can lead to significant morbidity and life‐threatening complications. ^1^ , ^2^ Tracheal resection (TR) and cricotracheal resection (CTR) are established surgical approaches for laryngotracheal stenosis. ^3^ However, they are associated with a 9% incidence of anastomotic complications, such as granulation tissue formation, anastomotic separation, and fistulae, which are linked to a 12‐fold increase in mortality risk. ^4^ , ^5^ , ^6^ , ^7^ , ^8^

The development of inflammatory granulation tissue at the site of airway resection can result in restenosis, with common management options being largely invasive in nature. ^9^ Specifically, rigid bronchoscopy with debridement, endoscopic laser ablation, and corticosteroid injections carry a considerable risk of iatrogenic injury. ^4^ Off‐label use of topical antibiotic‐corticosteroid medications, specifically Ciprodex (ciprofloxacin 0.3% and dexamethasone 0.1% otic suspension, Alcon Laboratories, Inc.), has been described primarily within neonatal and pediatric populations as a non‐invasive approach to reducing tracheal granulation tissue formation following tracheostomy, choanal atresia repair, and iatrogenic mucosal trauma. ^10^ , ^11^ Anecdotal use of these agents, typically administered via nebulization or direct application inside the tracheostomy tube, has also been reported in adult populations for tracheal granulation tissue prophylaxis after TR/CTR. ^12^ , ^13^ Nevertheless, the risk of adverse side effects has remained largely uncharacterized for the use of inhaled steroid medications in this setting.

Only one case series has evaluated the safety and side effect profile of a nebulized antibiotic‐corticosteroid agent for tracheal granulation tissue prophylaxis following TR/CTR in adults. ^13^ Additionally, the effectiveness of these agents in preventing tracheal granulation tissue formation and minimizing poor postoperative outcomes in clinical populations remains poorly understood. Thus, a national database was utilized to evaluate the association between the use of inhaled steroid medications postoperatively following TR/CTR and the risk of adverse side effects. Additionally, the analysis aimed to determine whether their use is linked to a lower incidence of granulation tissue formation and a reduced likelihood of subsequent surgical intervention of the airway.

Methods

Setting

A retrospective cohort study was performed using data from the US Collaborative Network in TriNetX Research Network (TriNetX, LLC). TriNetX is a global health‐collaborative clinical‐research platform, collects real‐time electronic medical record data from a network of healthcare organizations (HCOs). ^14^ The US Collaborative Network contains data from approximately 120 million patients from 69 HCOs nationwide within the United States. HCOs included hospitals, primary care units, and specialty care providers, with data encompassing both insured and uninsured patient populations. Available patient data included demographics, diagnoses (coded according to the International Classification of Diseases, Tenth Revision, Clinical Modification [ICD‐10‐CM]), procedures (Current Procedural Terminology [CPT], Healthcare Common Procedure Coding System [HCPCS], and medications [RxNorm]), and healthcare utilization. To ensure consistency and standardization across diverse data sources for the purposes of analysis, TriNetX employs automated mapping of institution‐specific coding systems. This enables uniform interpretation of data, thereby facilitating multicenter analyses and comparisons.

Ethics

TriNetX is compliant with the Health Insurance Portability and Accountability Act (HIPAA) and the General Data Protection Regulation. TriNetX is certified to the ISO 2013 standard and maintains an Information Security Management System to ensure the protection of accessible healthcare data and to fulfill requirements posed by the HIPAA Security Rule. TriNetX contains only aggregated counts and statistical summaries of de‐identified patient information, meeting the de‐identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. This study received appropriate institutional review board approval (University of Southern California Institutional Review Board, APP‐24‐06182). This study adhered to the tenets of the Declaration of Helsinki and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. ^15^

Cohort

Adult patients (age ≥ 18 years) undergoing first‐time TR/CTR as recorded within the TriNetX database between March 2005 to March 2025 were identified, as all data were extracted in March 2025. Using CPT codes, TR/CTR was defined as the following cricotracheal resection (CPT: 31592), tracheoplasty; cervical (CPT: 31750), tracheoplasty; intrathoracic (CPT: 31760), excision tracheal stenosis and anastomosis; cervical (CPT: 31780), excision tracheal stenosis and anastomosis; cervicothoracic (CPT: 31781).

The exposure was recipient of at least one of the following agents in topical, inhaled, or nebulized ciprofloxacin‐dexamethasone (RxNorm 2551), dexamethasone (RxNorm 3264, HCPCS J7638 and J7637), budesonide (RxNorm 19831, HCPCS J7634, J7633, J7627, J7626, J1096), fluticasone (RxNorm 41126), mometasone (RxNorm 108118), or beclomethasone (RxNorm 1347, HCPCS J7622). Patients who received agents within the first postoperative day following TR/CTR were eligible for study inclusion to align with the typical inpatient course for TR/CTR. ^16^ To minimize confounding, patients with diagnoses of asthma, otitis media, chronic obstructive pulmonary disease, allergic rhinitis, chronic rhinitis, nasopharyngitis, or pharyngitis within 3 months before or after the index surgery were excluded. Additionally, those who received any study agents within 1 month before TR/CTR were also excluded.

Outcome Measures

Outcomes were compared between patients receiving inhaled steroids following TR/CTR and those who did not. The primary outcome was safety, defined as a composite of adverse side effects, including the following asphyxiation (ICD‐10‐CM: T71), anaphylactic shock (ICD‐10‐CM: T78.2), angioneurotic edema (ICD‐10‐CM: T78.3), other and unspecified allergy (ICD‐10‐CM: T78.4), unspecified adverse effect of drug or medicament (ICD‐10‐CM: T88.7), symptoms and signs involving speech and voice (ICD‐10‐CM: R47‐R49), edema (ICD‐10‐CM: R60), headache (ICD‐10‐CM: R51), visual disturbances (ICD‐10‐CM: H53), localized swelling, mass and lump of skin and subcutaneous tissue (ICD‐10‐CM: R22), rash and other nonspecific skin eruption (ICD‐10‐CM: R21), and nausea and vomiting (ICD‐10‐CM: R11). Furthermore, patients with these diagnoses documented within 1 month before TR/CTR were excluded. Secondary outcome measures included tracheal granulation tissue formation (ICD‐10‐CM: L92.9, J95.09) and follow‐up surgical procedures involving the larynx, trachea, and/or bronchi, identified using broad category CPT codes (CPT: 1005814, 1005883) to ensure comprehensive capture. Patients with tracheal granulation tissue within 1 month before TR/CTR were also excluded. The time windows for outcome analyses included periods within 30 days and 3 months following TR/CTR.

Statistical Analysis

All statistical analyses were performed on the TriNetX platform. To minimize the effect of confounding factors, propensity score matching (PSM) was used to generate groups with matched baseline characteristics and comorbidities. Specifically, PSM was conducted based on age, sex, ethnicity (Hispanic/non‐Hispanic), race, tracheostomy status (ICD‐10‐CM: Z93.0), prior surgical procedures of the larynx, trachea, and/or bronchi (CPT: 1005814, 1005883), diseases of the vocal cords and larynx (ICD‐10‐CM: J38), overweight, obesity, and other hyperalimentation (ICD‐10‐CM: E65‐E68), diabetes mellitus (ICD‐10‐CM: E08‐E13), chronic lower respiratory diseases (ICD‐10‐CM: J40‐J4A), tobacco use (ICD‐10‐CM: Z72.0), hypertensive diseases (ICD‐10‐CM: I10‐I1A), diseases of the esophagus, stomach, and duodenum (ICD‐10‐CM: K20‐K31), diseases of the nervous system (ICD‐10‐CM: G00‐G99), metabolic disorders (ICD‐10‐CM: E70‐E88), heart diseases (ICD‐10‐CM: I30‐I5A), diseases of the blood and blood‐forming organs and certain disorders involving the immune mechanism (ICD‐10‐CM: D50‐D89), cerebrovascular diseases (ICD‐10‐CM: I60‐I69), acute kidney failure and chronic kidney disease (ICD‐10‐CM: N17‐N19), disorders of the thyroid gland (ICD‐10‐CM: E00‐E07), and diseases of the liver (ICD‐10‐CM: K70‐K77).

TriNetX utilizes greedy nearest‐neighbor matching with a caliper of 0.1 pooled standard deviations and a difference between propensity scores ≤ 0.1. Covariate balance between groups was assessed using standardized mean differences (SMDs). Any baseline characteristic with an SMD between cohorts lower than 0.1 is considered well‐matched. ^17^ All tests were two‐tailed with P < .05 considered statistically significant.

Results

A total of 2131 adults who underwent TR/CTR were identified, of whom 289 received inhaled steroids within the first postoperative day. The number of TR/CTR increased with time over the study period (2005‐2010: 172; 2010‐2015: 345; 2015‐2020: 735; and 2020‐2025: 879). Inhaled steroid use similarly increased with time over the study period (2005‐2010: 10; 2010‐2015: 27; 2015‐2020: 97; and 2020‐2025: 155). Before matching, patients in the steroid cohort had higher rates of comorbidities, including upper gastrointestinal diseases, chronic lower respiratory disease, and metabolic disorders (Table 1). Following PSM, 284 patients were included in the steroid cohort, and 284 patients were included in the control cohort. In the matched steroid cohort, the mean age was 39.7 ± 25.7 years, 45.4% were male, 72.5% identified as white, and 7.7% identified as Hispanic/Latino ethnicity. The prevalence of comorbid conditions tracheostomy status (29.6%), diseases of the vocal cords and larynx (51.1%), overweight and obesity (34.5%), diabetes mellitus (20.4%), chronic lower respiratory diseases (66.9%), hypertensive diseases (43.7%), diseases of the esophagus, stomach, and duodenum (71.8%), diseases of the nervous system (63.0%), metabolic disorders (47.2%), other forms of heart disease (30.3%), diseases of the blood and blood‐forming organs (38.4%), cerebrovascular diseases (7.4%), acute kidney failure and chronic kidney disease (16.5%), disorders of the thyroid gland (20.8%), and diseases of the liver (6.0%). Rates of systemic steroid use (treatment: 119 [41.9%]; 126 [44.3%]; P = .990) and systemic antibiotic use (treatment: 185 [65.1%]; 170 [59.9%]; P = .390) were comparable between cohorts.

Treatment with inhaled steroids was generally associated with a non‐significant reduction in the risk of adverse safety events, granulation tissue formation, and repeat airway surgery at both 30 days and 3 months following TR/CTR (Table 2). At 30 days, the odds of adverse safety events were similar between groups (OR 0.96, 95% CI: 0.56‐1.66, P = .890), and there was no difference in granulation tissue formation (OR 1.00, 95% CI: 0.41‐2.45, P = 1.000). However, at 30 days, the inhaled steroid group had 40% lower odds of requiring repeat airway surgery (OR 0.60, 95% CI: 0.42‐0.85, P = .004) (Figure 1). At 3 months, no significant differences were observed, with ORs of 0.79 (95% CI: 0.52‐1.21, P = .282) for safety, 0.85 (95% CI: 0.45‐1.62, P = .627) for granulation tissue, and 0.96 (95% CI: 0.68‐1.34, P = .797) for repeat airway surgery.

Discussion

Granulation tissue formation after TR/CTR is linked to adverse postoperative outcomes, potentially requiring additional invasive interventions such as tracheal stent placement or re‐operation, which can further increase the risk of morbidity and mortality. ^4^ , ^9^ The rising incidence of post‐resection granulation tissue development highlights the critical need for minimally invasive management strategies. ^6^ , ^16^ , ^18^ However, the off‐label use of inhaled steroid and steroid‐antibiotic medications has not yet been widely adopted in clinical practice due to uncertainties regarding safety and efficacy. To the best of our knowledge, this is the first multicentered retrospective study to investigate the association of inhaled steroid use post‐TR/CTR and safety outcomes, granulation tissue formation, and risk of future airway surgical intervention in an adult population.

The analysis found that the postoperative use of inhaled steroids was not associated with an increased risk of adverse side effects. In defining the composite safety outcome, a comprehensive approach was adopted by including a broad spectrum of diagnoses and symptoms—such as nonspecific complaints like headache, speech or voice changes, and nausea or vomiting—to ensure that potential side effects linked to corticosteroid agents would not be overlooked. Notably, these findings align with those of our previous case series, which reported a negligible incidence of side effects associated with the use of an antibiotic‐corticosteroid otic agent. ^13^ This is consistent with the general pharmacokinetics of inhaled corticosteroid and antibiotic formulations, where the risk of systemic absorption is minimal, and therapeutic action is largely localized to the site of application. ^19^ , ^20^ Furthermore, the relatively low systemic absorption of inhaled agents may help mitigate concerns regarding adverse effects typically associated with systemic corticosteroids or antibiotics, offering a safer alternative for managing localized complications in post‐TR/CTR patients. However, it is important to consider that heterogeneity in medication regimens and dosages could impact the generalizability of these findings, suggesting the need for more standardized protocols for inhaled steroid agent use in future research.

Interestingly, although postoperative administration of inhaled steroids was not significantly associated with reduced granulation tissue formation, it was significantly associated with a 40% reduction in the odds of repeat airway surgery within 30 days. Our findings align with prior pediatric evidence showing improved outcomes, including decreased length of stay and reduced need for postoperative bronchoscopy. ^21^ , ^22^ , ^23^ The absence of observed granulation tissue reduction may reflect limitations inherent to retrospective database studies (eg, inconsistent diagnostic documentation, lack of standardization of routine bronchoscopy evaluation across centers) or suggest that benefits may not specifically reflect reduced granulation tissue formation, but rather a general reduction in postoperative inflammation. Consistently, inhaled steroids have demonstrated significant attenuation of inflammation and bacterial colonization in wound healing models. ^24^ , ^25^ , ^26^ These findings highlight the need for further research on the use of inhaled steroid and steroid‐antibiotic (ie, Ciprodex) medications in adult TR/CTR patients for optimal therapeutic benefit.

This study has several limitations. As a retrospective cohort study using the TriNetX Research Network, the findings are constrained by the quality and completeness of available data, with potential misclassification or incomplete capture of diagnoses, procedures, or medication use. Furthermore, the observational design precludes causal inference, and despite extensive PSM—where matching accounted for numerous diagnoses and clinical variables just below the threshold of overmatching—residual confounding from unmeasured factors, such as provider practices or patient‐specific variables, may persist. Additionally, our exposure definition captured any inhaled steroid use within the first postoperative day without accounting for dosage variations, specific agents, or administration regimens—factors that may critically influence efficacy. Additionally, we excluded patients with tracheal granulation tissue 1 month before resection to improve data clarity, though these patients may have benefited from inhaled steroid therapy, and their exclusion could limit generalizability. Potential usage of mitomycin C and nebulized antibiotics was not studied and may have contributed to residual confounding. Similarly, the repeat airway procedure outcome may, in some cases, represent planned or routine postoperative interventions (eg, dilation, steroid injection) rather than solely complications requiring reintervention. Temporal variation in surgical practices over the study period could also have influenced outcomes, though these trends could not be specifically evaluated within the TriNetX platform. Furthermore, reliance on ICD‐10‐CM and CPT codes may overlook subtle clinical events not documented in electronic records. Nevertheless, the relatively large sample size and multicenter design enhance the generalizability of these findings, and the use of PSM improves analytic robustness.

Conclusion

In conclusion, this study provides important insights into the use of inhaled steroids and steroid‐antibiotic agents in the postoperative management of TR/CTR patients. Key findings demonstrate a favorable safety profile with no increased risk of adverse events and a 40% reduction in odds for repeat airway surgery in the first 30 days. Despite promising evidence, the lack of standardized treatment regimens may limit the observable efficacy of inhaled steroids in this population. Future studies with more controlled protocols are necessary to determine the optimal use of these agents in adult TR/CTR patients.

Author Contributions

Jason Shin Chwa and Alexander Tu Hong, conceptualization, data curation, formal analysis, investigation, methodology, validation, oringinal draft preparation, reivew and editing; Elizabeth Ann Shuman, conceptualization, methodology, reivew and editing; Karla O'Dell, conceptualization, methodology, project adminstration, supervision, validation, review and editing.

Disclosures

Competing interests

The authors declare no conflicts of interest.

Funding source

This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.