Association Between Red Blood Cell Distribution Width and Outcomes of Open Airway Reconstruction Surgery in Adults

Key Points

Question  Is red blood cell distribution width at the time of open airway reconstruction associated with the likelihood of achieving a prosthesis-free airway?

Findings  In this case series study of 92 patients with laryngotracheal stenosis who underwent open airway reconstruction, 74 were prosthesis free at last follow-up. Airway decannulation was significantly correlated with reduced red blood cell distribution width and the absence of posterior glottic stenosis.

Meaning  In adult patients undergoing open airway reconstruction, red blood cell distribution width may provide some insight into the preoperative probability of prosthesis removal and help patients make informed decisions.

Importance  Airway reconstruction for adults with laryngotracheal stenosis (LTS) is directed toward improving airway caliber to mitigate the patient’s dyspnea and achieve prosthesis-free breathing (ie, without tracheostomy, intraluminal stent, or T-tube). Despite the importance of preoperative risk stratification to minimize postoperative complications, consensus on an objective predictive algorithm for open airway reconstruction is lacking.

Objective  To determine whether the ability to achieve a prosthesis-free airway in adults after open airway reconstruction is associated with red blood cell distribution width (RDW) at the time of surgery.

Design, Setting, and Participants  Case series study investigating 92 consecutive patients 18 years and older with laryngotracheal stenosis who underwent open airway reconstruction at a US tertiary care hospital from January 1, 2006, to January 1, 2017.

Main Outcomes and Measures  The main outcome was a prosthesis-free airway (absence of tracheostomy, intraluminal stent, or T-tubes) at last follow-up. Multivariate logistic regression modeling was used to identify independent factors associated with this outcome.

Results  Of the 92 patients who met inclusion criteria, the median (interquartile range) age was 44 (33.0-60.3) years; 50 (53%) were female, and 82 (89%) were white. In all, 74 patients (80%) were prosthesis free at the last follow-up (mean, 833 days; 95% CI, 10-4229 days). In multivariate analyses, airway decannulation was significantly correlated with reduced RDW (odds ratio [OR], 0.40; 95% CI, 0.19-0.84) and the absence of posterior glottic stenosis (OR, 0.12; 95% CI, 0.04-0.37).

Conclusions and Relevance  These data suggest that surgical success in open airway reconstruction is significantly associated with RDW and whether the patient had posterior glottic stenosis. The RDW is a routine laboratory parameter that may provide some insight to the preoperative probability of prosthesis removal, facilitate risk stratification, promote informed patient decision making, and optimize health care resource management.

Laryngotracheal stenosis (LTS) is a life-threatening, fixed, extrathoracic restriction in pulmonary ventilation. It is an umbrella term that encompasses airway compromise at the level of the larynx, subglottis, or cervical trachea and is a common consequence of multiple pathophysiologic processes.^1-3 The goal of surgical treatment is to improve airway caliber to mitigate the patient’s dyspnea and achieve prosthesis-free breathing (eg, without tracheostomy, intraluminal stent, or T-tube).^2,4-10 Successful surgical outcomes depend on many factors, including technical expertise, pulmonary function, and patient characteristics.

Rates of achieving prosthesis-free breathing after adult open airway reconstruction surgery vary in the literature from 57% to 100%.¹⁰ With few exceptions,³ all LTS surgical studies have been small, single-institution case series. To date, variables associated with prosthesis-free breathing after LTS surgery include anatomical (eg, degree of luminal compromise, length of stenosis, and laryngeal involvement)^3,5 and patient-specific (eg, diabetes, obstructive sleep apnea, congestive heart failure, and gastroesophageal reflux disease) factors.^4,8 Despite the importance of preoperative risk stratification to minimize postoperative complications, consensus on an objective predictive algorithm for open airway reconstruction is lacking.

Red blood cell distribution width (RDW) is a biomarker that has been associated with a variety of surgical outcomes, including postoperative complications in resection of non–small cell lung cancer, aortic valve replacement, coronary artery bypass grafting, and partial hip replacement.^11-15 It has also been associated with all-cause mortality in critically ill patients.^16,17 It is hypothesized that RDW is a marker of systemic inflammation, although this association has not been fully elucidated. In otolaryngology, increased RDW at the time of hospital admission is associated with a worse prognosis of Bell palsy¹⁸ and idiopathic sudden sensorineural hearing loss.¹⁹ To date, no studies have evaluated the role of RDW in open airway reconstruction. The purpose of this study was to investigate whether RDW is associated with prosthesis-free breathing (ie, lack of tracheostomy, intraluminal stent, or T-tube) after open airway reconstruction in adults.

This case series study was approved by the Vanderbilt University Medical Center Institutional Review Board, which also waived the requirement for informed consent. Consecutive patients aged 18 years or older with LTS undergoing airway reconstruction from January 1, 2006, to January 1, 2017, at a tertiary care hospital were included. Patients were identified using Current Procedural Terminology codes 31580, 31587, 31588, 31582, 31592, 31780, and 31800. Two investigators (D.X.X., S.C.R.) independently extracted patient characteristics from the medical record, including components of the modified frailty index²⁰ (mFI) (eTable in the Supplement), RDW on the day of surgery, disease characteristics (morphologic features of the stenosis, McCaffrey grade^1,21,22), surgery type, follow-up duration, complications, and prosthesis-free breathing at last follow-up. The mFI is an 11-point scoring system that identifies patients who are more susceptible to postoperative complications. Scores range from 0 to 1, with a higher score (greater than 0.27) indicating an increased risk for complications. These data were entered into a secure REDCap (research electronic data capture; Vanderbilt University) database.

According to guiding principles beyond the scope of this study, the type of airway reconstruction was matched with the pathologic characteristics of the patient’s disease to maximize airway improvement while minimizing surgical morbidity.^23-27 Surgical operations for LTS were classified as tracheal resection, cricotracheal resection, extended resection (with concomitant posterior costal cartilage graft), tracheoplasty (using auricular cartilage to repair tracheocutaneous fistula), or laryngotracheal reconstruction (LTR). Laryngotracheal reconstructions were further categorized as an isolated posterior costal cartilage graft, endoscopic posterior costal cartilage graft, isolated anterior costal cartilage graft, or both anterior and posterior graft LTR. The primary outcome was prosthesis-free breathing at last follow-up (absence of tracheostomy, intraluminal stent, or T-tubes). Secondary outcomes included length of hospitalization, 30-day postoperative complications, and need for further airway procedures. Postoperative complications were defined as Clavien-Dindo classification grade III or greater.²⁸

Univariate analyses were performed using analysis of variance, Pearson χ² tests, and Fisher exact tests as appropriate. Stepwise multivariate logistic regression analysis was used to identify independent risk factors for prosthesis-free survival. Measures of significance were paired, and a significance level of P < .20 on univariate analysis was used as the criterion for variable inclusion in the multivariate model. Data were presented as effect sizes with CIs, and statistical significance was set at P < .05. All data analyses were done using Stata/MP version 12.1 (StataCorp).

Of the 92 patients who met the inclusion criteria, the median (IQR) age was 44 (33.0-60.3) years; 50 (54%) were female, and 82 (89%) were white. Of these, 89 (97%) had a McCaffrey grade of 2 or greater and 30 (33%) had posterior glottic stenosis (posterior glottic stenosis) (Table 1). Median mFI score was 0.09 (IQR, 0.00-0.18). Median (IQR) RDW was 13.7 μm (13.0-14.6 μm); reference range for RDW is 11.5-14.5 μm.

Patients were stratified by cause of stenosis into autoimmune, traumatic, iatrogenic, and idiopathic groups.³ Patients in whom stenosis developed after tracheostomy or within 2 years of intubation were classified as iatrogenic. Patients presenting with stenosis after traumatic injuries involving multiple organ systems (eg, gunshot wound) were classified as traumatic. Four patients with autoimmune or traumatic stenosis underwent reconstruction; univariate analyses compared outcomes between patients with idiopathic subglottic stenosis and iatrogenic stenosis. All 15 patients in the idiopathic group were women, compared with 33 of the 73 patients (45%) with iatrogenic stenosis. Patients in the idiopathic group also had a lower median mFI (0.09 vs 0.18; r = 0.04; 95% CI, −0.19 to 0.21) and RDW (13.9 vs 13.4; r = 0.20; 95% CI, −0.18 to 1.28) than those with iatrogenic LTS (Table 1). Patients with iatrogenic LTS had higher McCaffrey grades (3 or 4) (49 of 73 [67%] vs 5 of 15 [33%]; OR, 4.08; 95% CI, 1.26-13.28) and more often had a tracheostomy (64 of 73 [88%] vs 4 of 15 [27%]; OR, 0.05; 95% CI, 0.01-0.20) and posterior glottic stenosis (27 of 73 [37%] vs 2 of 15 [13%]; OR, 0.26; 95% CI, 0.05-1.25) compared with those with idiopathic subglottic stenosis (Table 1).

Tracheal resection was the most common procedure performed among the 92 patients in the series (38 [41%]), followed by LTR, which includes tracheoplasty, anterior and posterior costal cartilage graft, posterior costal cartilage graft, and endoscopic posterior costal cartilage graft (27 [29%]), cricotracheal resection (24 [26%]) and extended cricotracheal resection with PCCG (3 [3%]) (Table 2). Long-term success was considered to be prosthesis-free breathing (eg, without tracheostomy, intraluminal stent, or T-tube) at the last follow-up. Seventy-four patients (80%) had prosthesis-free breathing at the last follow-up (833 days; 95% CI, 10-4229 days).

In multivariate analysis, prosthesis-free breathing at last follow-up was associated with lower RDW (OR, 0.40; 95% CI, 0.19-0.84); for every 1-μm increase in RDW, the odds of achieving prosthesis-free breathing were decreased by a factor of 0.4. In addition, the absence of posterior glottic stenosis (posterior glottic stenosis, OR, 0.12; 95% CI, 0.04-0.37) and a lower mFI (r = 0.73, 95% CI, 0.00-0.18) were associated with achieving prosthesis-free breathing (Table 3).

When stratified by cause of stenosis, patients with iatrogenic stenosis had worse outcomes compared with patients with other causes (idiopathic subglottic stenosis) even when matched for McCaffrey grade (Table 4). The mean (SD) length of stay in the hospital was 7 (3.8) days. The 30-day postoperative course was uneventful for most patients, with 92.4% experiencing no complications. Red blood cell distribution width was not significantly associated with length of stay (r = 0.08; 95% CI, −0.40 to 1.52), postoperative complications (OR, 1.13; 95% CI, 0.43-2.84), or number of additional airway procedures after LTR (r = 0.20; 95% CI, −0.18 to 1.28).

Airway reconstruction is a diverse category of operations conceptually grouped into resection, augmentation (via cartilage grafting), and slide tracheoplasty. Although the desired outcome of airway reconstruction is clear (a prosthesis-free airway that adequately meets physiologic demands for ventilation, phonation, and deglutition), the indicators of operative success are less well defined.^1-10 Using univariate and multivariate analyses, we identified anatomic and physiologic factors associated with operative success. In this unique large cohort of adult patients undergoing open airway reconstruction, we showed that RDW was associated with operative success in airway reconstruction in patients with LTS.

Red blood cell distribution width has a well-established association with both all-cause^16,17 and procedure-specific mortality,^11-14,29 but a mechanistic explanation has not been definitively elucidated. It is probable that RDW serves as a surrogate measure for inflammation or underlying metabolic abnormalities, such as shortening of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia, hypertension, erythrocyte fragmentation, and alteration of erythropoietin function.¹⁶ Causes of increased RDW include anemia (iron, vitamin B₁₂, or folate deficiency; hemolytic anemia), bone marrow dysfunction, and liver disease.¹¹ However, the association between RDW and poor outcomes has been demonstrated independent of anemia and baseline hemoglobin levels.^11,29

Inflammatory cytokines, such as interleukin 6 and tumor necrosis factor, inhibit erythrocyte maturation and proliferation in addition to altering iron metabolism. In the 2 previously published otolaryngology studies investigating RDW and prognosis of Bell palsy¹⁸ and idiopathic sudden sensorineural hearing loss,¹⁹ the authors of both studies attributed inflammation as the most likely cause. Other studies consistently agreed that the most likely pathogenesis is related to either the inflammatory pathway or oxidative stress.

Despite the knowledge gap in the precise pathophysiologic process connecting increased RDW values to systemic inflammation, RDW is an ideal biomarker owing to its ubiquity, low cost, and literature base. Future work will evaluate the association between surgical outcome and alternate biomarkers of systemic inflammation (eg, C-reactive protein, fibrinogen, D-dimer, and serum interleukin 6) to more fully phenotype patients with LTS and further refine preoperative risk stratification.

Posterior glottic stenosis typically arises after endotracheal tube–related pressure injury to the thin posterior glottic mucosa,³⁰ which leads to exposed cartilage and disordered wound healing, culminating in pathologic contracture that manifests as physiologic ventilatory restriction.³¹ Surgical therapies are aimed at static enlargement of the laryngeal inlet, although endoscopic posterior glottic scar removal with bilateral temporary arytenoid adduction have been posited as an alternative for select patients.³² The tools, technique, and procedures available to rebuild the scarred and immobile larynx are inadequate. Our results reinforce the consequences that laryngeal injuries have on the ability to live without an airway prosthesis. Our findings should both spur innovation in new reconstructive techniques and heighten vigilance in the intensive care unit to prevent the initial injury from occurring. Both animal models³³ and clinical case series have demonstrated an association of posterior glottic stenosis with procedural variables, including increased duration of intubation^34,35 and increased endotracheal tube size.^34-36 These are proven modifiable risk factors that can be addressed through process-based institutional efforts.

This study also validates previously published observations in LTS in a new patient cohort.³ In that series of patients, when stratifying decannulation based on cause of stenosis, patients with iatrogenic had worse outcomes compared with those with idiopathic LTS, even when matched for stenosis grade. These new data reinforce the concept that although different mechanisms of airway injury physiologically affect the patient in similar ways, they occur in unique populations and have divergent responses to therapy.

Owing to the inherent constraints involved in surgical research, the retrospective nature of this case series study has limitations, including the restricted number of patients studied and the lack of an a priori defined treatment protocol. Within the cohort, there were few patients with high frailty. Adams et al³⁷ also noted a similar pattern of low frailty in patients undergoing all otolaryngology procedures, possibly reflecting the overall health of the subspecialty’s patient population. However, despite the predominance of low mFI scores, multivariate modeling robustly identified an association of lower mFI with prosthesis-free survival. In addition, as with any retrospective study looking at time-to-event data, our study has the potential for right-sided and left-sided censoring bias. However, with a mean follow-up of 833 days from surgery, we believe that the period of observation was sufficient to mitigate against this risk.

Although defining surgical success as airway decannulation is a widely accepted metric for procedural outcome, it is likely equally critical that the patient’s experience with treatment be systematically characterized. This series of patients lacks patient-reported outcomes for dyspnea, voicing, and swallowing. However, an ongoing study within the North American Airway Collaborative (noaac.net) is aimed at providing patient-centered data on the disease survivorship experience in laryngotracheal stenosis.

Our analysis suggests that lower RDW is associated with surgical success in adult patients undergoing open airway reconstruction for LTS. Although prospective study with external validation is needed, these readily quantified metrics may offer an objective assessment of preoperative risk, facilitating improved risk stratification and counseling regarding surgical outcomes.

Accepted for Publication: November 5, 2018.

Corresponding Author: Christopher T. Wootten, MD, Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN 37232 (christopher.t.wootten@vumc.org).

Published Online: January 10, 2019. doi:10.1001/jamaoto.2018.3793

Author Contributions: Drs Xie and Wootten had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rehman, Garrett, Gelbard.

Study concept and design: Wootten.

Acquisition, analysis, or interpretation of data: Xie, Rehman, Francis, Netterville, Garrett, Gelbard, Lipscomb.

Drafting of the manuscript: Xie, Rehman, Francis, Gelbard, Wootten.

Critical revision of the manuscript for important intellectual content: Rehman, Francis, Netterville, Garrett, Lipscomb, Wootten.

Statistical analysis: Xie, Rehman, Francis, Gelbard, Lipscomb, Wootten.

Administrative, technical, or material support: Garrett, Gelbard.

Study supervision: Wootten.

Supervision: Netterville, Garrett, Gelbard, Lipscomb.

Conflict of Interest Disclosures: None reported.

Funding/Support: This was a North American Airway Collaborative (NoAAC) Study. Research in NoAAC is made possible by infrastructure supported by the Patient-Centered Outcomes Research Institute under award number 1409-22214. The research also used REDCap software, which was funded by grant UL1 TR000445 from the National Center for Advancing Translational Sciences of the National Institutes of Health.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors.

Meeting Presentation: These data were presented as an abstract at the American Academy of Otolaryngology–Head & Neck Surgery Annual Meeting; September 11, 2017; Chicago, Illinois.