Airway Dilator Research Articles

Prospective Assessment of Safety, Tolerance, and Perceptions of Awake Airway and Esophageal Dilation.

An increasing number of laryngeal and esophageal procedures are being performed as "awake" procedures (non-general anesthesia), with some under local anesthesia, including in clinic. While high tolerance and safety profiles have been reported for various laryngeal procedures, few studies directly assess tolerability of awake dilation procedures of the upper esophagus (UE) and laryngotracheal airway (LTA). Prospective, open-label. Prospectively collected patient and physician surveys from a tertiary laryngology center recorded patient tolerance, safety, and perceptions of awake UE and LTA balloon dilation. Fifty-six awake procedures were performed on 41 patients, including 46 UE and 20 LTA dilations. All procedures were successfully completed. Overall pain was mild (3.5 ± 2.4/10, ranging 0 = no pain to10 = worst pain) and the dilation itself was reportedly the most painful portion (4.1 ± 2.9/10). Patient satisfaction with the procedure was high (7.0 ± 2.2/10, ranging 0 = worst to 10 = best experience). Most patients would undergo the procedure again (73.6%) and would recommend the procedure to others (89.3%). Patient-reported tolerance was similar immediately postoperatively and at follow-up. LTA and UE dilation patients reported similar levels of tolerance. Awake upper esophageal balloon dilation is a safe, well-tolerated procedure with high completion and patient satisfaction rates. Similarly, early experience with awake laryngotracheal airway balloon dilation suggests comparable favorability, although careful consideration of patient selection and procedural implementation is strongly recommended to optimize and protect patient safety. 3 Laryngoscope, 2024.

Uncovering Diaphragm Cramp in SIDS and Other Sudden Unexpected Deaths.

The diaphragm is the primary muscle of respiration. Here, we disclose a fascinating patient's perspective that led, by clinical reasoning alone, to a novel mechanism of spontaneous respiratory arrests termed diaphragm cramp-contracture (DCC). Although the 7-year-old boy survived its paroxysmal nocturnal "bearhug pain apnea" episodes, essentially by breathing out to breathe in, DCC could cause sudden unexpected deaths in children, especially infants. Diaphragm fatigue is central to the DCC hypothesis in SIDS. Most, if not all, SIDS risk factors contribute to it, such as male sex, young infancy, rebreathing, nicotine, overheating and viral infections. A workload surge by a roll to prone position or REM-sleep inactivation of airway dilator or respiratory accessory muscles can trigger pathological diaphragm excitation (e.g., spasms, flutter, cramp). Electromyography studies in preterm infants already show that diaphragm fatigue and sudden temporary failure by transient spasms induce apneas, hypopneas and forced expirations, all leading to hypoxemic episodes. By extension, prolonged spasm as a diaphragm cramp would induce sustained apnea with severe hypoxemia and cardiac arrest if not quickly aborted. This would cause a sudden, rapid, silent death consistent with SIDS. Moreover, a unique airway obstruction could develop where the hypercontracted diaphragm resists terminal inspiratory efforts by the accessory muscles. It would disappear postmortem. SIDS autopsy evidence consistent with DCC includes disrupted myofibers and contraction band necrosis as well as signs of agonal breathing from obstruction. Screening for diaphragm injury from hypoxemia, hyperthermia, viral myositis and excitation include serum CK-MM and skeletal troponin-I. Active excitation could be visualized on ultrasound or fluoroscopy and monitored by respiratory inductive plethysmography or electromyography.

Radiomultiomics: quantitative CT clusters of severe asthma associated with multi-omics.

Lung quantitative computed tomographic (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways. We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterize radiomultiomic-associated clusters (RACs). qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated BMI, mild airflow limitation, normal qCT parameters and upregulation of the complement pathway. RAC2 (n=34) subjects had a lower degree of airflow limitation, airway wall thickness and dilatation, with upregulation of proliferative pathways, including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B (NTRK2/TRKB), and down-regulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signaling and signaling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9. U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent anovel strategy to identify new molecular pathways in asthma pathobiology.

The activity of suprahyoid muscles during sevoflurane-induced gasping in mice

Sevoflurane-induced gasping in mice involves an enormous increase in inspiratory effort, mandibular movement, and a marked decrease in respiratory frequency (fR). We examined differences in breathing patterns and electromyogram activity (EMGSH) of the suprahyoid muscles (SHMs) during eupnea under 3.2 % (1 MAC: minimum alveolar concentration) sevoflurane inhalation and sevoflurane-induced gasping under 6.5 % (2 MAC) sevoflurane inhalation in eight spontaneously breathing, tracheally intubated, adult mice. We found that the phasic EMGSH is obtained only during inspiration in eupnea and gasping and that integrated EMGSH increases more, as a percent of baseline (% baseline) than tidal volume (VT) during gasping (median [interquartile range]; integrated EMGSH: 720 [425–1965] vs. VT: 300 [238–373], P < 0.05). We also found that the onset of EMGSH precedes the start of airflow while maintaining a bell-shaped EMGSH contour, which characterizes the EMG of upper airway dilator (UAD) muscles during eupnea and gasping. Vigorous respiratory-related mandibular movements were never observed during eupnea but were observed in seven of 8 mice during sevoflurane-induced gasping. Our observations indicate that SHMs act as a preferentially activating UAD muscle, contributing to the development of mandibular respiratory movements.

Motor control of the palatoglossus and genioglossus during changes in breathing route.

High activity of upper airway dilator muscles is thought to be critical in preventing sleep-related upper airway collapse. To date, most of the research regarding upper airway dilator muscles has focused on the genioglossus muscle, which protrudes the tongue and opens the retroglossal airway. However, collapse commonly occurs in the retropalatal region. We therefore aimed to examine the motor control of the palatoglossus muscle as well as investigate breathing route-related changes in genioglossus and palatoglossus motor units. Single motor unit recordings of the genioglossus and palatoglossus were made simultaneously in healthy individuals during wakefulness while breathing through the nose with the mouth closed (NMC), nose with mouth open (NMO) or orally (OMO). The palatoglossus was found to have all 5 motor unit firing patterns that have been observed in other upper airway dilator muscles, but during nasal breathing had a higher proportion of tonically active but inspiratory modulated motor units as compared to the genioglossus (67% vs 30%). When still breathing nasally but with the mouth open, the units with an expiratory firing pattern in genioglossus, and all firing patterns in palatoglossal, increased their firing rates compared to nasal breathing with the mouth closed (GG: 17.8±4.9 vs 23.1±4.8 Hz, PG: 17.0±4.0 vs 19.3±4.0 Hz). Finally, oral breathing resulted in dramatic reductions in the number of palatoglossal motor units that were firing (35 units vs 92 during nasal breathing). Palatoglossus activity may contribute importantly to airway collapsibility and may provide an alternate pathway for preventing sleep-related airway collapse.

Orthodontic perspectives of obstructive sleep apnea

OSA is defined as a condition in which there is repetitive partial or complete collapse of the pharynx during sleep. An apnea is defined as an almost complete (at least 90%) cessation of airflow, and hypopnea is defined as a reduction in nasal pressure amplitude of at least 50% and/ or a reduction in thoracoabdominal movement of 50% or more for a minimum of 10 seconds. Often, patients first seek an otorhinolaryngologic (ENT) evaluation rather than presenting to a sleep center. Normal sleep involves air passing through and going directly down to the lungs. With an obstructed airway, the structures in the back of the throat (the tongue, the tonsils, and/or adenoids) occlude the airway due to an inadequate motor tone of the tongue and/or airway dilator muscles, and thus, prevent the air from passing. The aetiology is multifactorial, and the main risk factors in children include adenotonsillar hypertrophy, obesity, neuromuscular disorders and craniofacial anomalies. Adenotonsillar hypertrophy is the most commonly reported aetiological factor. Therefore, the treatment of choice for paediatric OSA is adenotonsillectomy. In adulthood, the use of oral appliances is a treatment option in the management of OSA

Stimulation of the internal superior laryngeal nerve as a potential therapy for obstructive sleep apnea in a porcine model.

Impaired pharyngeal sensing of negative pressure (NP) can lead to a blunted response of the upper airway dilator muscles and contribute to the development of obstructive sleep apnea (OSA). This response is modulated by the nerve fibers in the internal branch of the superior laryngeal nerve (iSLN), mediating negative pressure sensation. Artificial excitation of these fibers could be a potential treatment target for OSA. To evaluate this, electrostimulation of the iSLN was performed in a porcine-isolated upper airway model. Artificial obstructions were induced by varying the levels of negative pressure, and the ability of the animal to resolve these obstructions was evaluated. The pressure at which the animal was still able to resolve the obstruction was quantified as "Resolvable Pressure." Thereby, the effects on pharyngeal patency (n = 35) and the duration of the therapeutic effect outlasting the stimulation (n = 6) were quantified. Electrostimulation before the introduction of an artificial obstruction improved the median resolvable pressure from -28.3 cmH2O [IQR: -45.9; -26.1] to -92.6 cmH2O [IQR: -105.1; -78.6]. The median therapeutic effect was found to outlast the last stimulation burst applied by 163 s when five stimulation bursts were applied in short succession [IQR: 58; 231], 58 s when two were applied [IQR: 7; 65], and 6 s when one was applied [IQR: 0; 51]. Stimulation of the iSLN increased electromyography (EMG) in the genioglossus (GG). The proposed treatment concept can improve pharyngeal patency in the model. Transfer of the results to clinical application could enable the development of a new neuromodulation therapy for OSA.NEW & NOTEWORTHY Electrostimulation before the introduction of an artificial obstruction to induce artificial sleep apnea in the pig model improves the response of the upper airway to negative pressure (NP). The electrostimulation creates a sustained therapeutic effect that outlasts the initial electrostimulation. The use of this therapy in clinical practice has the potential to treat obstructive sleep apnea (OSA).

GOLD-Grade Specific Disease Characterization and Phenotyping of COPD Using Quantitative Computed Tomography in the Nationwide COSYCONET Multicenter Trial in Germany

Introduction: The aim of this study was to apply quantitative computed tomography (QCT) for GOLD-grade specific disease characterization and phenotyping of air-trapping, emphysema, and airway abnormalities in patients with chronic obstructive pulmonary disease (COPD) from a nationwide cohort study. Methods: As part of the COSYCONET multicenter study, standardized CT in ex- and inspiration, lung function assessment (FEV1/FVC), and clinical scores (BODE index) were prospectively acquired in 525 patients (192 women, 327 men, aged 65.7 ± 8.5 years) at risk for COPD and at GOLD1–4. QCT parameters such as total lung volume (TLV), emphysema index (EI), parametric response mapping (PRM) for emphysema (PRMEmph) and functional small airway disease (PRMfSAD), total airway volume (TAV), wall percentage (WP), and total diameter (TD) were computed using automated software. Results: TLV, EI, PRMfSAD, and PRMEmph increased incrementally with each GOLD grade (p < 0.001). Aggregated WP5–10 of subsegmental airways was higher from GOLD1 to GOLD3 and lower again at GOLD4 (p < 0.001), whereas TD5–10 was significantly dilated only in GOLD4 (p < 0.001). Fifty-eight patients were phenotyped as “non-airway non-emphysema type,” 202 as “airway type,” 96 as “emphysema type,” and 169 as “mixed type.” FEV1/FVC was best in “non-airway non-emphysema type” compared to other phenotypes, while “mixed type” had worst FEV1/FVC (p < 0.001). BODE index was 0.56 ± 0.72 in the “non-airway non-emphysema type” and highest with 2.55 ± 1.77 in “mixed type” (p < 0.001). Conclusion: QCT demonstrates increasing hyperinflation and emphysema depending on the GOLD grade, while airway wall thickening increases until GOLD3 and airway dilatation occur in GOLD4. QCT identifies four disease phenotypes with implications for lung function and prognosis.

Therapeutic Management of Bronchiectasis in Children and Adolescents: A Concise Narrative Review.

Introduction: Bronchiectasis, characterized by airway dilation, mucus hypersecretion, and recurrent exacerbations, is increasingly recognized in children and adolescents. Recent guidelines from the European Respiratory Society (ERS) and Thoracic Society of Australia and New Zealand (TSANZ) emphasize early diagnosis and optimized management. This review explores therapeutic strategies for pediatric bronchiectasis. Materials and methods: Our review involved a comprehensive search of English-language literature in the PubMed and EMBASE databases until December 2023, focusing on observational studies, interventions, reviews, and guidelines in pediatric bronchiectasis. Results: Management strategies encompass airway clearance techniques, mucoactive agents, pulmonary rehabilitation, bronchodilators and inhaled corticosteroids tailored to individual needs and age-appropriate techniques. Antibiotics play key roles in preventing exacerbations, eradicating pathogens, and managing acute exacerbations, which are guided by culture sensitivities and symptoms. Long-term antibiotic prophylaxis, particularly macrolides, aims to reduce exacerbations, although concerns about antibiotic resistance persist. Vaccinations, including pneumococcal and influenza vaccines, are crucial for preventing infections and complications. Surgery and lung transplantation are reserved to severe, refractory cases after failure of medical therapies. Conclusions: The optimal management of pediatric bronchiectasis requires a multidisciplinary approach, including physiotherapy, pharmacotherapy, and vaccinations, tailored to individual needs and guided by evidence-based guidelines. Further research is needed to refine diagnostic and therapeutic strategies and improve outcomes for affected children and adolescents.

Effect of BAL Lipoxin A4 Level in Children with Bronchiectasis on Disease Severity

Abstract Background A central feature of most cases of bronchiectasis is airway inflammation. The elevated neutrophil count has been strongly correlated with impaired lung function, bronchiectasis severity, and disease duration. There is a failure of resolution of inflammation in bronchiectasis, leading to irreversible damage and dilatation of the bronchial airways with loss of mucociliary function. Lipoxins were the first agents to be identified as anti-inflammatory endogenous lipid mediators involved in the resolution of inflammation. Aim of the Work This study aimed to measure Lipoxin A4 level in bronchoalveolar lavage (BAL) of children with Cystic Fibrosis bronchiectasis (CF) and Non-CF bronchiectasis as a prognostic marker for clinical and radiological severity in these children as regard Bronchiectasis severity score. Methods A cross-sectional study was conducted at Children’s Hospital, Ain Shams University from December 2020 to December 2021, on children following up at the Pediatric Pulmonology Clinic. The study included 15patients with cystic fibrosis (CF) bronchiectasis, 15 patients with non-CF bronchiectasis, and 30 control cases,without breathing difficulty or signs of RDS. Human Lipoxin A4 was measured in BAL by ELISA. Results There was a significant difference between patients and controls as regards Lipoxin A4 level (p = 0.002),being higher in control group, but no significant difference in its level between CF and non-CF bronchiectasischildren(p = 0.663). Conclusion Severe bronchiectasis is associated with decreased airway Lipoxin A4 levels as lowest level of lipoxinA4 was found in severe cases by bronchiectasis severity score.

In vivo MRI and PET imaging in a translational ILD mouse model expressing non-resolving fibrosis and bronchiectasis-like pathology after repeated systemic exposure to bleomycin.

C57BL/6 mice received bleomycin (i.p. 35iU/kg) or saline as control twice per week for 4 weeks. Mice were monitored until 2 weeks after cessation of bleomycin administration (w4 + 1 and w4 + 2), referred to as the resting period. MRI scans were performed in weeks 3 and 4 and during the resting weeks. [18F]FDG-PET was performed at the last week of dosing (w4) and 2 weeks after the last dosing (w4 + 2). Lung tissue sections were stained with Masson's trichrome and evaluated by modified Ashcroft scoring. Lung volume and lesion volumes were assessed using MRI, as well as 3D mapping of the central airways. Bleomycin-challenged mice showed increased lung weights (p < 0.05), while total lung volume was unchanged (w4 and onward). Histology analysis demonstrated fibrotic lesions emanating from the distal parts of the lung. Fibrosis progression was visualized by MRI with significantly increased high signal in bleomycin-exposed lungs compared to controls (p < 0.05). In addition, a significant increase in central airway diameter (p < 0.01) was displayed in bleomycin-exposed animals compared to controls and further continued to dilate as the disease progressed, comparing the bleomycin groups over time (p < 0.05-0.001). Lung [18F]FDG uptake was significantly elevated in bleomycin-exposed mice compared to controls (p < 0.05). Non-invasive imaging displayed progressing lesions in the lungs of bleomycin-exposed mice, using two distinct MRI sequences and [18F]FDG-PET. With observed fibrosis progression emanating from distal lung areas, dilation of the central airways was evident. Taken together, this chronic bleomycin-exposure model is translationally more relevant for studying lung injury in ILD and particularly in the context of DIILD.

Mounier-Kuhn syndrome: A case report of a 64-year-old male followed up after 8 years of the first diagnosis

Mounier-Kuhn Syndrome (MKS) is a rare congenital disorder characterized by the abnormal dilatation of the major airways, namely trachea and stem bronchi. It can be presented as the recurrent lower respiratory tract infection. Symptoms may vary from being asymptomatic to a wide range of infections which may lead to severe respiratory failure. Diagnosis can be performed by the means of computed tomography and bronchoscopy. The treatment is primarily symptomatic and supportive. Herein, we have presented a case of a 64-years old man, ex-smoker, who was referred after 4 episodes of antibiotic treated pulmonary infection. He was previously diagnosed with tracheobronchomegaly through CT scan in 2015. We have compared the lung function test and the radiological features between two time slots being 8 years apart (2015-2023), that showed insignificant change.

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Efficacy of the ExVent Accessory for the O2Vent Optima Oral Appliance in the Treatment of Obstructive Sleep Apnea

Study Objectives: An optional accessory for the O2Vent Optima mandibular advancement device, the ExVent, provides oral expiratory positive airway pressure (EPAP). Similar to nasal EPAP, oral EPAP results in passive airway dilatation, reducing flow limitation. The present study was conducted to evaluate the safety and efficacy of the ExVent accessory for the treatment of mild to moderate obstructive sleep apnea (OSA). Methods: This prospective, multicenter, open-label, single-arm study enrolled participants diagnosed with mild to moderate OSA (defined as apnea–hypopnea index [AHI] 5–29). During the Home Use Phase, study participants logged their hours of O2Vent Optima + ExVent usage at home over 3 months. Participants were then evaluated by in-laboratory polysomnogram while using the O2Vent Optima + ExVent. The primary effectiveness measure was a change in AHI relative to baseline while using the O2Vent Optima + ExVent. Results: Treatment with the O2Vent Optima + ExVent improved AHI by 62% on average, from 15.3 (interquartile range [IQR]: 11.5–19.5) to 5.8 (IQR: 3.9–6.8; p&lt;0.001). Mean oxygen saturation improved from 93.5%±1.2% to 94.6%±1.34% (p=0.006). The lowest oxygen saturation increased from 85% (IQR: 83%–87%) to 90% (IQR: 89%–95; p&lt;0.001). The overall treatment success rate (AHI&lt;5) was 66%, and the treatment response rate (&gt;50% reduction in AHI) was 77%. No excessive adverse events or device malfunction events were reported. Conclusions: Use of the O2Vent Optima with the ExVent oral EPAP accessory successfully reduced AHI in mild to moderate OSA with no significant adverse effects.

The Effect of an Increasing Subglottal Stenosis Constriction That Extends From the Vocal Folds to the Inferior Border of the Cricoid Cartilage.

Acquired subglottal stenosis is an unpredicted complication that can occur in some patients who have undergone prolonged endotracheal intubation. It is a narrowing of the airway at the level of the cricoid cartilage that can restrict airflow and cause breathing difficulty. Stenosis is typically treated with endoscopic airway dilation, with some patients experiencing multiple recurrences. The study highlights the potential of computational fluid dynamics as a noninvasive method for monitoring subglottic stenosis, which can aid in early diagnosis and surgical planning. An anatomically accurate human laryngeal airway model was constructed from computerized tomography (CT) scans. The subglottis cross-sectional area was narrowed systematically using ≈10% decrements. A quadratic profile was used to interpolate the transformation of the airway geometry from its modified shape to the baseline geometry. The numerical results were validated by static pressure measurements conducted in a physical model. The results show that airway resistance follows a squared ratio that is inversely proportional to the size of the subglottal opening (R∝A-2). The study found that critical constriction occurs in the subglottal region at 70% stenosis (upper end of grade 2). Moreover, removing airway tissue below 40% stenosis during surgical intervention does not significantly decrease airway resistance.

Osteopathic Manipulative Treatment for Chronic Bronchiectasis

Bronchiectasis is an uncommon chronic obstructive lung disease caused by chronic airway inflammation leading to irreversible bronchial dilation and destruction of medium-sized airways. In this case, we treated a bronchiectasis patient with a combination of osteopathic manipulative treatment (OMT) techniques including myofascial release and lymphatic techniques as adjunctive treatments in addition to other pharmacologic and nonpharmacologic therapies; OMT was shown to improve subjective symptoms of airway congestion as well as reduce frequency of emergency room visits and hospital admissions for this patient.

Regional associations between inspiratory tongue dilatory movement and genioglossus activity during wakefulness in people with obstructive sleep apnoea.

Inspiratory tongue dilatory movement is believed to be mediated via changes in neural drive to genioglossus. However, this has not been studied during quiet breathing in humans. Therefore, this study investigated this relationship and its potential role in obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue dilatory movement, quantified with tagged magnetic resonance imaging, and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in nine controls [apnoea-hypopnea index (AHI) ≤5 events/h] and 37 people with untreated OSA (AHI >5 events/h). Measurements were obtained for 156 neuromuscular compartments (85%). Analysis was adjusted for nadir epiglottic pressure during inspiration. Only for 106 compartments (68%) was a larger anterior (dilatory) movement associated with a higher phasic EMG [mixed linear regression, beta=0.089, 95% CI [0.000, 0.178], t(99)=1.995, P=0.049, hereafter EMG↗/mvt↗]. For the remaining 50 (32%) compartments, a larger dilatory movement was associated with a lower phasic EMG [mixed linear regression, beta=-0.123, 95% CI [-0.224, -0.022], t(43)=-2.458, P=0.018, hereafter EMG↘/mvt↗]. OSA participants had a higher odds of having at least one decoupled EMG↘/mvt↗ compartment (binary logistic regression, odds ratio [95% CI]: 7.53 [1.19, 47.47] (P=0.032). Dilatory tongue movement was minimal (>1 mm) in nearly all participants with only EMG↗/mvt↗ compartments (86%, 18/21). These results demonstrate that upper airway dilatory mechanics cannot be predicted from genioglossus EMG, particularly in people with OSA. Tongue movement associated with minimal genioglossus activity suggests co-activation of other airway dilator muscles. KEY POINTS: Inspiratory tongue movement is thought to be mediated through changes in genioglossus activity. However, it is unknown if this relationship is altered by obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue movement, quantified with tagged magnetic resonance imaging (MRI), and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in four tongue compartments of people with and without OSA. Larger tongue anterior (dilatory) movement was associated with higher phasic genioglossus EMG for 68% of compartments. OSA participants had an ∼7-times higher odds of having at least one compartment for which a larger anterior tongue movement was not associated with a higher phasic EMG than controls. Therefore, higher genioglossus phasic EMG does not consistently translate into tongue dilatory movement, particularly in people with OSA. Large dilatory tongue movements can occur despite minimal genioglossus inspiratory activity, suggesting co-activation of other pharyngeal muscles.

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways

IntroductionThe standard therapy for bronchial asthma consists of combinations of acute (short-acting ß2-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß2-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological TH2-phenotype in asthma, acting—at least partially—through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease.MethodsAfter stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function.ResultsOur results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1−/−) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol.ConclusionAmitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.

O043 Investigating Upper-Airway Mechanics with Computational Tongue Models

Abstract With the use of computational models of the oral cavity, we aim to understand how changes in the morphology of the oral cavity and changes the stiffness of the tongue affect the movement of the posterior surface of the tongue. Anatomical and diffusion weighted imaging from 20 healthy individuals (10M:10F, Age: 22-54years, BMI: 17-30kg/m²), were used to develop 3D models of the tongue including the fibre orientations of the tongue muscles. All models were aligned and scaled to match the volume of the average subject's mandible, so that only differences in shape were modelled. The muscles of the tongue were modelled as transversely isotropic, with a shear moduli of 2.9 and 1.0kPa, parallel and perpendicular to the muscle fibre direction, respectively. Each individual participant model was prescribed an active contraction producing 50kPa of stress in the horizontal component of the genioglossus. The influence of initial hyoid position on the average anterior displacement of the posterior surface of the tongue was assessed with linear regression. On average the contraction moved the posterior tongue 4.0±0.7mm anteriorly. For every millimetre of hyoid elevation, anterior tongue displacement (i.e. airway dilation) decreased by 0.1mm. These initial models demonstrate that the automated modelling pipeline can identify how structural differences alter the efficacy of dilator muscles. Future implementations of these models will also incorporate experimentally measured pharyngeal pressures, and temporal and spatial patterns of muscle activations based on experimental data, to assess the how variation in the coordinated contractions contributes to airway collapse.

Acute nasal breathing lowers diastolic blood pressure and increases parasympathetic contributions to heart rate variability in young adults.

There is growing interest in how breathing pace, pattern, and training (e.g., device-guided or -resisted breathing) affect cardiovascular health. It is unknown whether the route of breathing (nasal vs. oral) affects prognostic cardiovascular variables. Because nasal breathing can improve other physiological variables (e.g., airway dilation), we hypothesized that nasal compared with oral breathing would acutely lower blood pressure (BP) and improve heart rate variability (HRV) metrics. We tested 20 adults in this study [13 females/7 males; age: 18(1) years, median (IQR); body mass index: 23 ± 2 kg·m-2, means ± SD]. We compared variables between nasal- and oral-only breathing (random order, five min each) using paired, two-tailed t tests or Wilcoxon signed-rank paired tests with significance set to P < 0.05. We report the median (interquartile range) for diastolic BP and means ± SD for all other variables. We found that nasal breathing was associated with a lower mean BP (nasal: 84 ± 7 vs. oral: 86 ± 5 mmHg, P = 0.006, Cohen's d = 0.70) and diastolic BP [nasal: 68(8) vs. oral: 72(5) mmHg, P < 0.001, Rank-biserial correlation = 0.89] but not systolic BP (nasal: 116 ± 11 vs. oral: 117 ± 9 mmHg, P = 0.48, Cohen's d = 0.16) or heart rate (HR; nasal: 74 ± 10 vs. oral: 75 ± 8 beats·min-1, P = 0.90, Cohen's d = 0.03). We also found that nasal breathing was associated with a higher high-frequency (HF) contribution to HRV (nasal: 59 ± 19 vs. oral: 52 ± 21%, P = 0.04, Cohen's d = 0.50) and a lower low frequency-to-HF ratio at rest (nasal: 0.9 ± 0.8 vs. oral: 1.2 ± 0.9, P = 0.04, Cohen's d = 0.49). These data suggest that nasal compared with oral breathing acutely 1) lowers mean and diastolic BP, 2) does not affect systolic BP or heart rate, and 3) increases parasympathetic contributions to HRV.NEW & NOTEWORTHY There is growing interest in how breathing pace, pattern, and training (e.g., device-guided or -resisted breathing) affect prognostic cardiovascular variables. However, the potential effects of the breathing route on prognostic cardiovascular variables are unclear. These data suggest that nasal compared with oral breathing 1) lowers mean and diastolic blood pressure (BP), 2) does not affect systolic BP or heart rate (HR), and 3) increases parasympathetic contributions to heart rate variability (HRV). These data suggest that acute nasal breathing improves several prognostic cardiovascular variables.