Risk factors and impact of swallowing impairment and aspiration after lung transplantation

Introduction

Lung transplantation is a life-saving procedure for patients with end-stage lung disease (ESLD). According to the Organ Procurement & Transplantation Network (OPTN; 2023), 3,026 individuals underwent lung transplantation in the United States in 2023, and that number is projected to steadily increase (1). Despite advances in the transplant procedure, aspiration, or the entry of foreign material into the trachea or lungs, is a prevalent complication following lung transplantation (2-7). Post-prandial aspiration, or aspiration of esophageal or stomach contents, has been well-studied in the lung transplant population. Prandial aspiration, or aspiration of food and liquids as a result of oropharyngeal swallowing impairment, has recently gained more attention due to its association with acute and long-term complications after lung transplant, such as increased length of stay, re-admission to the intensive care unit, and discharge to dependent care (2,4,6). Pulmonary function is also impaired by the consequences of aspiration, which is a known risk factor for developing chronic lung allograft dysfunction (CLAD), the leading cause of late mortality in lung transplant recipients (8).

Prior studies exploring this underrecognized complication have found that between 67–100% of patients demonstrate laryngeal penetration or aspiration due to oropharyngeal dysphagia after lung transplantation (2-7,9,10). Furthermore, airway invasion is often clinically undetectable, as it occurs silently or without physiologic response. Intubation and thoracic procedures can cause direct and indirect injury to the larynx and vagal nerve (11,12), making lung transplant patients susceptible to sensorimotor deficits and compromised airway protection post-operatively. Premorbid risk factors for dysphagia, such as frailty (13,14), disrupted respiratory swallow coordination (15,16), and decreased laryngeal sensitivity (17,18) are also common in patients with ESLD and may predispose patients to more significant swallowing complications after lung transplant. Despite this awareness, procedures for evaluating the swallowing function of lung transplant recipients vary within and between medical institutions, limiting the generalizability of findings and true estimation of dysphagia after lung transplantation (6).

The purpose of this study was to characterize the severity of airway invasion identified on instrumental swallow evaluations and explore potential risk factors associated with aspiration after lung transplantation. The nature of swallowing impairment was also described to elucidate the potential pathophysiology of airway invasion post-lung transplantation. Additionally, we aimed to evaluate the potential impact of airway invasion on short- and long-term post-operative outcomes with the underlying hypothesis that patients with unsafe swallowing would have poorer outcomes. This study may guide future investigations and aid in the development of standardized protocols for the evaluation of swallowing after lung transplantation. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-707/rc).

Methods

Study design

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Northwestern University (STU00207250, STU00213616, and STU00215512) and written consent was waived due to the retrospective study design. A single site, cross-sectional review was conducted for all patients over 18 years of age who had a single or bilateral lung transplantation between January 2018 and December 2022 and received a Modified Barium Swallow Study (MBSS) or Flexible Endoscopic Evaluation of Swallowing (FEES) following lung transplantation. Data were collected from the electronic medical record and a clinical lung transplant database at the Northwestern University Medical Center in Chicago, Illinois, USA.

Measures of oropharyngeal swallowing impairment and airway invasion

At the time of this study, patients that demonstrated clinical indicators of aspiration or were suspected to be at greater risk for aspiration (e.g., intubated >48 hours, underwent tracheostomy, required high flow oxygen therapy) after lung transplantation were referred for a swallow evaluation by a Speech-Language Pathologist (SLP). Swallow evaluations were not routinely conducted during the pre-operative evaluation for lung transplantation, and not all patients were referred for testing after transplantation. In our center, Northwestern Memorial Hospital, patients with connective tissue disease or severe esophageal dysmotility underwent gastro-jejunal tube placement before lung transplant and were not referred for a swallow evaluation during their immediate post-operative recovery. For patients referred for a swallow evaluation, the type of instrumental swallow study conducted was determined through careful consideration of patient-related factors (e.g., ability to transfer to radiology, pain, lines/tubes) and the clinical question. Per standard of care, MBSS were administered and analyzed using the Modified Barium Swallow Impairment Profile (MBSImP™) protocol (19) by two certified SLPs (achieved >80% inter-rater reliability). The FEES exams were also conducted and interpreted by two trained SLPs using a modified version of the Langmore protocol (20).

The maximum Penetration-Aspiration Scale (PAS) scores were reported for both MBSS and FEES. The PAS is a validated ordinal scale (1, absence of airway invasion; 8, silent aspiration) that captures the presence, degree, and response to airway invasion (Table S1) (21). Scores of 1–2 are considered within normal variation in healthy adults (22), therefore, scores were dichotomized into safe (PAS 1–2) and pathological airway invasion (PAS ≥3).

MBSImP scores were reported for MBSS only. The standardized and validated scoring metric includes 17 physiologic swallowing components rated on an ordinal scale. The highest (most severe) score contributes to the overall impression (OI) score for each component (19).

Definition of complication

Primary graft dysfunction (PGD)

The definition of PGD is based on the 2016 International Society for Heart and Lung Transplantation (ISHLT) guideline (23). Patients with no evidence of pulmonary edema on chest X-ray (CXR) are classified as grade 0. The lack of mechanical ventilation was quantified according to the ratio of PaO₂ to FiO₂. In the absence of PaO₂ data, an oxygen saturation/FiO₂ ratio was employed for the calculation of the PaO₂/FiO₂ ratio. Grade 1: PaO₂/FiO₂ ratio >300; Grade 2: PaO₂/FiO₂ ratio =200–300; Grade 3: PaO₂/FiO₂ ratio <200. The lowest PaO₂/FiO₂ ratio observed within 72 hours after lung transplantation was utilized. The application of extracorporeal membrane oxygenation (ECMO) for bilateral pulmonary edema as depicted on CXR images was classified as grade 3, while the continuous use of ECMO in the absence of pulmonary edema on CXR imaging was excluded.

CLAD

In accordance with the 2019 ISHLT consensus document on the nomenclature of CLAD and its clinical phenotypes (8), CLAD was identified as a persistent decline (≥20%) in the measured forced expiratory volume in 1 second (FEV₁) from the post-transplantation baseline. Patients with fewer than three total FEV₁ measurements were excluded from analysis, as this was insufficient to diagnose CLAD.

Acute kidney injury (AKI)

The definition of AKI was based on the risk, failure, loss of kidney function, and end-stage kidney disease classification (24).

Statistical analysis

A comparison was made between patients with safe swallowing and those with airway invasion (PAS ≥3) on MBSS and FEES, with regard to recipient and donor characteristics, preoperative laboratory values, and intra- and post-operative outcomes. The Chi-squared test was employed to assess the statistical significance of categorical variables, which were presented as numerical values and percentages. Univariate logistic regression analyses were utilized to assess the ability of recipient characteristics to predict airway invasion. Subsequently, a multivariate logistic regression analysis was conducted utilizing variables from the univariate logistic regression analyses with a P value <0.2. Odds ratio (OR) and 95% confidence interval (CI) were reported. The Kaplan-Meier method was used to estimate survival, and the log-rank test was performed to compare survival between the groups. Statistical significance was set at P<0.05. Receiver operating characteristic (ROC) curves were plotted using variables identified as predictors of airway invasion. The performance of the two models were compared using the DeLong test (25). The EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), was utilized to conduct all the analyses (26).

Results

Oropharyngeal swallowing

Of the 251 patients that underwent a single or bilateral lung transplant during the study period, 118 received an instrumental swallow study (79 FEES, 39 MBSS) post-operatively and were included in this study. Airway invasion (PAS ≥3) was observed in 59% (70/118) of patients (Table 1). Of the patients with airway invasion, 46% (32/70) demonstrated laryngeal penetration (PAS 3–5) and 54% (38/70) aspirated. Silent aspiration (PAS 8) occurred in 68% (26/38) of aspiration events.

All patients that had a MBSS (39/118 patients with instrumental exam) had delayed initiation of the pharyngeal swallow (component 6) (Table 2). Many patients who underwent a MBSS also demonstrated oral residue (30/39; component 5), partial laryngeal elevation (30/39; component 8), incomplete laryngeal vestibular closure (27/39; component 11), and incomplete pharyngoesophageal segment opening (27/39; component 14), all of which can contribute to laryngeal penetration or aspiration.

Patients

Patient characteristics are summarized in Table 3 (lab values obtained before transplantation are summarized in Table S2). Body mass index (BMI) and body surface area (BSA) were collected at the time of listing for lung transplantation. Patients with airway invasion had significantly lower BMI (24.7±4.5 vs. 26.8±4.6 kg/m², P=0.02), lower BSA (1.8±0.2 vs. 1.9±0.2 m², P=0.02), and a greater frequency of preoperative hypertension (52.9% vs. 31.3%, P=0.03). No other significant differences were identified between patients with safe swallowing and those with airway invasion.

Intra- and post-operative outcomes

Intra- and post-operative outcomes were similar between patients with safe swallowing and patients with airway invasion (Table 4). The median follow-up for this cohort is 431 (Q1–Q3, 194–705) days. The survival curves are shown in Figure 1. There were no significant differences between the two curves using the Wilcoxon signed-rank test (P=0.69).

Figure 1 Survival curves of patients with safe swallowing vs. airway invasion. The survival curves for patients with safe swallowing and those with airway invasion demonstrated no significant differences between the two curves (P=0.69).

Risk factors associated with airway invasion

Univariate logistic regression analysis revealed that BMI (OR 0.91, 95% CI: 0.83–0.99, P=0.02), BSA (OR 0.13, 95% CI: 0.02–0.76, P=0.02), and hypertension (OR 2.47, 95% CI: 1.14–5.33, P=0.02) before transplantation were predictors of airway invasion after lung transplantation (Table S3). In subsequent multivariate logistic regression analysis, hypertension (OR 2.62, 95% CI: 1.09–6.29, P=0.03) was an independent predictor of airway invasion (Table 5).

ROC analysis to identify the cutoff value

A post-hoc ROC analysis was performed to identify and evaluate the cut off value of BMI and BSA to predict airway invasion. Sensitivity, specificity, and predictive values are demonstrated in Figure S1A,S1B. BMI gave an AUC of 0.63 (95% CI: 0.52–0.73) with cut off 23.9 kg/m², and BSA gave an AUC of 0.64 (95% CI: 0.53–0.74) with cut off 1.74 m² for predicting airway invasion. There was no significant difference between the two ROC curves (P=0.93) (Figure S1C).

Discussion

Swallowing impairment resulting in laryngeal penetration and aspiration occurred with high frequency (59% of patients) in this cohort of patients following lung transplantation. Iatrogenic injury to the recurrent laryngeal nerve and superior laryngeal nerve, which provide motor and sensory innervation to the larynx, can occur from trauma during intubation, intubation with large (>8 mm) or double lumen endotracheal tubes, or traction injury during surgery. Such injuries may disrupt sensorimotor function of the larynx and increase risk of silent aspiration after cardiothoracic procedures (12,27,28). Our results reflect the presence of sensorimotor disruption, as we found that 68% of aspirators had no cough in response to aspiration (PAS 8), consistent with the high rates of silent aspiration reported in other studies. It is plausible that aspiration may have gone undetected in patients without clinical indicators of aspiration who were not referred for an instrumental swallow evaluation and, therefore, not included in our study, and the prevalence of airway invasion may in fact be higher.

The MBSS reveal possible physiologic mechanisms of airway invasion after lung transplantation, including delayed initiation of the pharyngeal swallow, reduced hyolaryngeal excursion, and incomplete distention of the pharyngoesophageal segment. Reedy et al. [2023] found similar swallowing impairments in a cohort of patients after lung transplantation, reporting that most patients initiated the pharyngeal swallow when the bolus head reached the pyriform sinuses (MBSImP component 6, score of 3), and demonstrated partial laryngeal elevation (MBSImP component 8, score 1) and incomplete laryngeal vestibular closure (MBSImP component 11, score 1) (7). The identification of the specific swallowing impairments contributing to aspiration are critical for selection of appropriate interventions to rehabilitate swallowing and minimize aspiration. As suggested in previous literature, one potential etiology of these specific impairments is the injury to the vagal nerve due to manipulation of the aerodigestive tract and surgical procedures (2-7). However, it has recently been hypothesized that atypical respiratory-swallow coordination may also play a role in swallowing impairment after lung transplant (7,10). Respiration and swallowing are two tightly coupled, critical functions of the body that likely have bidirectional interactions. In healthy adults, swallowing occurs during the expiratory phase of the respiratory cycle at mid-to-low tidal lung volumes, and expiration resumes after a brief respiratory cessation that occurs during the swallow (29,30). This respiratory-swallow pattern, expiration-swallow-expiration, provides a biomechanical advantage for swallowing, facilitating swallowing safety and bolus clearance (31). Given the significant changes in respiratory mechanics that occur as a result of ESLD and lung transplant surgery and the specific swallowing impairments exhibited in this cohort, alterations in respiratory-swallow coordination may be another potential contributor to swallowing impairment and aspiration after lung transplantation.

Patients undergoing lung transplantation are a heterogenous group, and there are likely several patient and clinical factors that influence post-operative swallowing safety. Our results suggested statistically significant associations between BMI, BSA, and hypertension and airway invasion, however, their clinical significance requires further exploration. Malnutrition occurs in patients with ESLD and can manifest as sarcopenia and reduced exercise endurance as pulmonary severity increases (32). In studies of dysphagic adults, low BMI, malnutrition, and frailty have been linked to swallowing impairment (33). As swallowing consists of highly synchronized skeletal and smooth muscular activity, changes in muscle composition and physical endurance may influence swallowing kinematics and timing and ultimately make patients with lower BMI more susceptible to airway invasion upon further deconditioning after lung transplantation. Although several studies have identified hypertension as a common comorbidity in dysphagic adults, the underpinnings of the linkage between swallowing and hypertension are not clear. One potential mechanism may be the use of calcium channel blockers as a treatment for hypertension. Calcium channel blockers have been shown to reduce lower esophageal sphincter pressure, increase esophageal acid exposure, and induce hypomotility in patients without history of esophageal dysfunction (34). As there is a functional interrelationship between oropharyngeal and esophageal swallowing, it is possible that the use of calcium channel blockers may result in disruptions along the entire swallowing continuum (35). Further investigation is needed to better understand how anti-hypertension medications may impact oropharyngeal swallowing. Although not statistically significant, the risk of airway invasion was roughly 2.6 times greater in patients with a history of interstitial lung disease (ILD), signaling that the type of lung disease necessitating lung transplantation may influence swallowing impairment. Other factors that have been found to be associated with airway invasion in previous investigations of swallowing after lung transplantation include preoperative gastroesophageal reflux, longer intubation durations, reintubation after surgery, tracheostomy, and the intraoperative use of venovenous (VV)-ECMO (6,9). Our study did not confirm these associations; however, sampling method and the small sample size may have contributed to the discrepancy.

Our results indicate that post-operative outcomes and survival rates were similar among patients with safe swallowing and those with airway invasion detected upon instrumental swallow assessment. Patients with airway invasion (PAS 3–8) were treated conservatively and risk stratification with the transplant surgeon, pulmonologist, and SLP helped to determine whether an oral diet would be initiated. This process took into consideration the patient’s cognitive status, physical conditioning, and respiratory status (e.g., values on incentive spirometry, supplemental oxygen needs, airway clearance). Many patients with aspiration were kept nil per os (NPO), received enteral nutrition, underwent pulmonary toileting, and were closely monitored to protect lung function and promote recovery after lung transplantation. Diet advancement occurred when there was evidence of improvement in airway protection and overall conditioning. It is possible that this collaborative approach to clinical management in patients with airway invasion may have minimized the negative consequences of aspiration, thus resulting in similar post-operative outcomes between the two groups.

The primary limitations of this study were the retrospective study design and patient selection methods. Although all patients that received an instrumental swallow evaluation were included, not all patients who underwent lung transplantation were referred for swallow assessment. During the study period, only patients with clinical signs of swallowing impairment or aspiration were referred for MBSS or FEES. It can be argued that selective referral for instrumental assessment after this complex procedure likely underestimates the true prevalence of airway invasion after lung transplantation (2,3,6,10). Future investigations should include prospective evaluation of swallowing with consideration of baseline swallowing function, swallowing pathophysiology, and respiratory-swallow coordination in order to optimize oropharyngeal swallowing function before and after lung transplantation.

Conclusions

A high prevalence of silent aspiration was observed after lung transplantation. Although associations between BMI and hypertension and airway invasion were statistically significant, additional work is needed to better understand these relationships and their clinical significance. Post-operative outcomes were found to be similar between patients with safe swallowing and those with airway invasion. This is thought to be due to aggressive clinical management following identification of aspiration, which may have mitigated the impact of airway invasion on post-operative recovery. The high frequency of airway invasion in this study and the likelihood of undetected aspiration in the patients that were not referred for swallow assessment influenced a change in clinical practice at our institution. Instrumental swallow studies are now routinely conducted for all patients after lung transplantation, which allows for characterization of the specific physiologic impairments contributing to airway invasion and the selection of specific, evidenced-based interventions to improve swallowing function and reduce risk of aspiration-related complications.

Acknowledgments

Funding: This work was supported by the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health (NIH/NIDCD 2K24DC012801-0).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-707/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-707/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-707/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-707/coif). B.M.H. receives grant funding from the National Institutes of Health (2K24DC012801-07, 1R01CA262502- 01, 1R01DK122975-01) and Bracco Diagnostics Inc., royalties from Northern Speech Services and the Medical University of South Carolina Foundation for Research Development, and consulting fees from Bracco Diagnostics Inc. She holds a US Provisional Patent for wearable sensor technology (US 62/710,324). A.B. is supported by the National Institutes of Health, HL145478, HL147290, and HL147575. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Northwestern University (STU00207250, STU00213616, and STU00215512) and written consent was waived due to the retrospective study design.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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