Pharyngeal Muscle Responses Research Articles

P002 Targeted non-CPAP combination therapy resolves obstructive sleep apnoea

Abstract Introduction Mandibular advancement splint (MAS) therapy is an effective alternative to CPAP for many people with obstructive sleep apnoea (OSA) but ~50% have residual OSA. This study aimed to resolve OSA in these individuals by combining MAS with other targeted therapies based on OSA endotype characterisation. Methods Eleven people with OSA (apnoea-hypopnoea index (AHI): 35±13 events/h), not fully resolved with MAS alone (AHI>10 events/h) were recruited. Initially, OSA endotypes were assessed via a detailed physiology night. Step one of combination therapy focused on anatomical interventions including MAS plus an oral expiratory positive airway pressure valve (EPAP) and a supine-avoidance device. Participants with residual OSA (AHI>10 events/h) following the anatomical combination therapy night, were then given one or more targeted non-anatomical therapies according to endotype characterisation. This included oxygen (4L/min) to reduce unstable respiratory control (high loop gain), 10mg zolpidem to increase arousal threshold, or 80/5mg atomoxetine-oxybutynin (ato-oxy) for poor pharyngeal muscle responsiveness. Results OSA was successfully treated (AHI<10 events/h) in all participants with combination therapy. MAS combined with EPAP and supine-avoidance therapy resolved OSA in ~65% of participants (MAS alone vs. combination therapy: 17±4 vs. 5±3, events/h, n=7). For the remaining participants, OSA resolved with the addition of oxygen (n=2), one with 80/5mg ato-oxy and another required both oxygen and 80/5mg ato-oxy. Discussion Targeted combination therapy may be a viable treatment alternative for people with OSA who cannot tolerate CPAP or for those who have an incomplete therapeutic response with monotherapy.

The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial.

Recent animal and human physiology studies indicate that noradrenergic and muscarinic processes are key mechanisms that mediate pharyngeal muscle control during sleep. The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, whether these findings translate to the clinically relevant patient population of people with obstructive sleep apnoea (OSA), and the effects of the agents on OSA severity, are unknown. We found that reboxetine plus hyoscine butylbromide reduced OSA severity, including overnight hypoxaemia, via increases in pharyngeal muscle responsiveness, improvements in respiratory control and airway collapsibility without changing the respiratory arousal threshold. These findings provide mechanistic insight into the role of noradrenergic and anti-muscarinic agents on upper airway stability and breathing during sleep and are important for pharmacotherapy development for OSA. The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, the effects of this drug combination on obstructive sleep apnoea (OSA) severity are unknown. Accordingly, this study aimed to determine if reboxetine plus hyoscine butylbromide reduces OSA severity. Secondary aims were to investigate the effects on key upper airway physiology and endotypic traits. Twelve people with OSA aged 52±13years, BMI=30±5kg/m2 , completed a double-blind, randomised, placebo-controlled, crossover trial (ACTRN12617001326381). Two in-laboratory sleep studies with nasal mask, pneumotachograph, epiglottic pressure sensor and bipolar fine-wire electrodes into genioglossus and tensor palatini muscles were performed separated by approximately 1week. Each participant received either reboxetine (4mg) plus hyoscine butylbromide (20mg), or placebo immediately prior to sleep. Polysomnography, upper airway physiology and endotypic estimates of OSA were compared between conditions. Reboxetine plus hyoscine butylbromide reduced the apnoea/hypopnoea index by (mean±SD) 17±17events/h from 51±30 to 33±22events/h (P=0.005) and nadir oxygen saturation increased by 6±5% from 82±5 to 88±2% (P=0.002). The drug combination increased tonic genioglossus muscle responsiveness during non-REM sleep (median [25th, 75th centiles]: -0.007 [-0.0004, -0.07] vs. -0.12 [-0.02, -0.40] %maxEMG/cmH2 O, P=0.02), lowered loop gain (0.43±0.06 vs. 0.39±0.07, P=0.01), and improved airway collapsibility (90 [69, 95] vs. 93 [88, 96] %eupnoea, P=0.02), without changing the arousal threshold (P=0.39). These findings highlight the important role that noradrenergic and muscarinic processes have on upper airway function during sleep and the potential for pharmacotherapy to target these mechanisms to treat OSA.

Orofacial Myofunctional Therapy in Obstructive Sleep Apnea Syndrome: A Pathophysiological Perspective.

Obstructive sleep apnea (OSA) syndrome is a multi-factorial disorder. Recently identified pathophysiological contributing factors include airway collapsibility, poor pharyngeal muscle responsiveness, a low arousal threshold, and a high loop gain. Understanding the pathophysiology is of pivotal importance to select the most effective treatment option. It is well documented that conventional treatments (continuous positive airway pressure (CPAP), upper airway surgery, and dental appliance) may not always be successful in the presence of non-anatomical traits, especially in mild to moderate OSA. Orofacial myofunctional therapy (OMT) consists of isotonic and isometric exercises targeted to oral and oropharyngeal structures, with the aim of increasing muscle tone, endurance, and coordinated movements of pharyngeal and peripharyngeal muscles. Recent studies have demonstrated the efficacy of OMT in reducing snoring, apnea–hypopnea index, and daytime sleepiness, and improving oxygen saturations and sleep quality. Myofunctional therapy helps to reposition the tongue, improve nasal breathing, and increase muscle tone in pediatric and adult OSA patients. Studies have shown that OMT prevents residual OSA in children after adenotonsillectomy and helps adherence in CPAP-treated OSA patients. Randomized multi-institutional studies will be necessary in the future to determine the effectiveness of OMT in a single or combined modality targeted approach in the treatment of OSA. In this narrative review, we present up-to-date literature data, focusing on the role of OSA pathophysiology concepts concerning pharyngeal anatomical collapsibility and muscle responsiveness, underlying the response to OMT in OSA patients.

Recording drug responses from adult Dirofilaria immitis pharyngeal and somatic muscle cells

Despite being considered one of the most pathogenic helminth infections of companion animals, members of macrocyclic lactone class are the only drugs available for the prevention of heartworm disease caused by Dirofilaria immitis. Alarmingly, heartworm prevention is at risk; several studies confirm the existence of macrocyclic lactone resistance in D. immitis populations across the United States.To safeguard the long term prevention and control of this disease, the identification and development of novel anthelmintics is urgently needed. To identify novel, resistance-breaking drugs, it is highly desirable to:Unfortunately, none of the three above statements can be answered sufficiently for D. immitis and most of our hypotheses derive from surrogate species and/or in vitro studies. Therefore, the present study aims to improve our fundamental understanding of the neuromuscular system of the canine heartworm by establishing new methods allowing the investigation of body wall and pharyngeal muscle responses and their modulation by anthelmintics. We found that the pharynx of adult D. immitis responds to both ivermectin and moxidectin with EC50s in the low micromolar range. We also demonstrate that the somatic muscle cells have robust responses to 30 μM acetylcholine, levamisole, pyrantel and nicotine. This is important preliminary data, demonstrating the feasibility of electrophysiological studies in this important parasite.

A Novel Model to Estimate Key Obstructive Sleep Apnea Endotypes from Standard Polysomnography and Clinical Data and Their Contribution to Obstructive Sleep Apnea Severity.

Rationale: There are at least four key pathophysiological endotypes that contribute to obstructive sleep apnea (OSA) pathophysiology. These include 1) upper-airway collapsibility (Pcrit); 2) arousal threshold; 3) loop gain; and 4) pharyngeal muscle responsiveness. However, an easily interpretable model to examine the different ways and the extent to which these OSA endotypes contribute to conventional polysomnography-defined OSA severity (i.e., the apnea-hypopnea index) has not been investigated. In addition, clinically deployable approaches to estimate OSA endotypes to advance knowledge on OSA pathogenesis and targeted therapy at scale are not currently available.Objectives: Develop an interpretable data-driven model to 1) determine the different ways and the extent to which the four key OSA endotypes contribute to polysomnography-defined OSA severity and 2) gain insight into how standard polysomnographic and clinical variables contribute to OSA endotypes and whether they can be used to predict OSA endotypes.Methods: Age, body mass index, and eight polysomnography parameters from a standard diagnostic study were collected. OSA endotypes were also quantified in 52 participants (43 participants with OSA and nine control subjects) using gold-standard physiologic methodology on a separate night. Unsupervised multivariate principal component analyses and data-driven supervised machine learning (decision tree learner) were used to develop a predictive algorithm to address the study objectives.Results: Maximum predictive performance accuracy of the trained model to identify standard polysomnography-defined OSA severity levels (no OSA, mild to moderate, or severe) using the using the four OSA endotypes was approximately twice that of chance. Similarly, performance accuracy to predict OSA endotype categories ("good," "moderate," or "bad") from standard polysomnographic and clinical variables was approximately twice that of chance for Pcrit and slightly lower for arousal threshold.Conclusions: This novel approach provides new insights into the different ways in which OSA endotypes can contribute to polysomnography-defined OSA severity. Although further validation work is required, these findings also highlight the potential for routine sleep study and clinical data to estimate at least two of the key OSA endotypes using data-driven predictive analysis methodology as part of a clinical decision support system to inform scalable research studies to advance OSA pathophysiology and targeted therapy for OSA.

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity.

A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10mgzolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6±12.3 vs. 40.3±16.4events/h (means±SD), p=0.938) or nadir oxyhaemoglobin saturation (79.6±6.6 vs. 79.7±7.4%,p=0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9±14%(83±11 vs. 73±17%, p=0.010). Arousal threshold increased by 15±5% with zolpidem throughout all sleep stages (p=0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia.

Obstructive Sleep Apnea: Epidemiology, Causes, and Consequences

As part one of the three chapters on sleep-disordered breathing, this chapter reviews obstructive sleep apnea (OSA) epidemiology, causes, and consequences. When comparing OSA prevalence between 1988 to 1994 and 2007 to 2010, we observe that OSA is rapidly on the rise, paralleling increasing rates in obesity. Global epidemiologic studies indicate that there are differences specific to ethnicity with Asians presenting with OSA at a lower body mass index than Caucasians. We have learned that structural and physiologic factors increase the risk of OSA and both can be influenced by genetics. Structural risk factors include craniofacial bony restriction, changes in fat distribution, and the size of the upper airway muscles. Physiologic risk factors include airway collapsibility, loop gain, pharyngeal muscle responsiveness, and arousal threshold. The consequences of OSA include daytime sleepiness and exacerbation of many underlying diseases. OSA has been associated with cardiovascular diseases including hypertension, coronary heart disease, stroke, atrial fibrillation, and other cardiac arrhythmias; pulmonary hypertension; metabolic disorders such as type 2 diabetes, hypothyroidism, acromegaly, Cushing syndrome, and polycystic ovarian syndrome; mild cognitive impairment or dementia; and cancer. This review contains 4 figures, 1 table and 48 references. Key Words: cardiac consequences, craniofacial bony restriction, epidemiology, fat distribution, metabolic disease, neurodegeneration, obesity, obstructive sleep apnea

Morphine alters respiratory control but not other key obstructive sleep apnoea phenotypes: a randomised trial.

Accidental opioid-related deaths are increasing. These often occur during sleep. Opioids such as morphine may worsen obstructive sleep apnoea (OSA). Thus, people with OSA may be at greater risk of harm from morphine. Possible mechanisms include respiratory depression and reductions in drive to the pharyngeal muscles to increase upper airway collapsibility. However, the effects of morphine on the four key phenotypic causes of OSA (upper airway collapsibility (pharyngeal critical closure pressure; P crit), pharyngeal muscle responsiveness, respiratory arousal threshold and ventilatory control (loop gain) during sleep) are unknown.21 males with OSA (apnoea-hypopnoea index range 7-67 events·h-1) were studied on two nights (1-week washout) according to a double-blind, randomised, cross-over design (ACTRN12613000858796). Participants received 40 mg of MS-Contin on one visit and placebo on the other. Brief reductions in continuous positive airway pressure (CPAP) from the therapeutic level were delivered to induce airflow limitation during non-rapid eye movement (REM) sleep to quantify the four phenotypic traits. Carbon dioxide was delivered via nasal mask on therapeutic CPAP to quantify hypercapnic ventilatory responses during non-REM sleep.Compared to placebo, 40 mg of morphine did not change P crit (-0.1±2.4 versus -0.4±2.2 cmH2O, p=0.58), genioglossus muscle responsiveness (-2.2 (-0.87 to -5.4) versus -1.2 (-0.3 to -3.5) μV·cmH2O-1, p=0.22) or arousal threshold (-16.7±6.8 versus -15.4±6.0 cmH2O, p=0.41), but did reduce loop gain (-10.1±2.6 versus -4.4±2.1, p=0.04) and hypercapnic ventilatory responses (7.3±1.2 versus 6.1±1.5 L·min-1, p=0.006).Concordant with recent clinical findings, 40 mg of MS-Contin does not systematically impair airway collapsibility, pharyngeal muscle responsiveness or the arousal threshold in moderately severe OSA patients. However, consistent with blunted chemosensitivity, ventilatory control is altered.

Dose-dependent effects of mandibular advancement on upper airway collapsibility and muscle function in obstructive sleep apnea.

Mandibular advancement splints (MAS) are the leading treatment alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). However, not all patients experience clinical benefit and treatment prediction remains challenging. Understanding the effects of mandibular advancement on pharyngeal collapsibility and muscle function may provide valuable information on the mechanisms of MAS, and thereby help to develop novel approaches for patient selection. Thus, we aimed to determine dose-dependent effects of mandibular advancement on pharyngeal collapsibility and muscle function concurrently in OSA patients undergoing MAS therapy. Twelve (11 male) MAS-naïve patients underwent a detailed physiology sleep study (polysomnography) to quantify pharyngeal collapsibility (PCRIT), pharyngeal muscle responsiveness to negative pharyngeal pressure (via genioglossus intramuscular electromyography and an epiglottic pressure sensor) and effectiveness to restore airflow and minute ventilation (Vi) after 1-minute transient CPAP reductions (induced airflow-limitation) at three mandibular advancement positions: 0% (habitual bite), 50% and 100% of the maximum comfortable mandibular advancement. Standard clinical polysomnography after MAS therapy optimization was performed to determine treatment outcome. Overall, participants were obese with severe OSA (mean ± SD: BMI = 31 ± 4 kg/m2, apnea-hypopnea index [AHI] = 33 ± 14 events/hour). PCRIT decreased with mandibular advancement in a dose-dependent manner (1.8 ± 3.9 vs. -0.9 ± 2.9 vs. -4.0 ± 3.6 cmH2O; p < 0.001). There was no systematic change in genioglossus muscle responsiveness (p = 0.09) or effectiveness to restore peak airflow (p = 0.4) or Vi (p = 0.7) with mandibular advancement. Mandibular advancement reduces pharyngeal collapsibility in a dose-dependent manner without systematically changing genioglossus muscle function in a predominantly obese and severe OSA population. This indicates that the primary mode of action of MAS therapy is via improvement in passive pharyngeal anatomy.

OSA Endotypes: What Are They and What Are Their Potential Clinical Implications?

To review critically the different mechanisms, or endotypes, causing obstructive sleep apnea (OSA) in individual patients, and their potential implications for management. Currently, at least four underlying mechanisms that contribute to OSA have been identified, namely a compromised upper airway anatomy, a poor pharyngeal muscle responsiveness, respiratory control instability (high loop gain), and a low arousal threshold (wake up too easily); the relative contributions of these four traits in an individual form their endotype. Endotypes provide therapeutic targets that may facilitate development of novel therapies, can predict treatment response to non-CPAP therapies, and may explain clinical phenotypes. Endotyping is currently restricted to specialized research laboratories, but newer methods relying on standard polysomnography may soon allow routine assessment of endotypes as part of clinical practice. Endotyping promises to transform the current one-size fits-all OSA management into an individualized precision medicine approach in the future.

Arousal Intensity is a Distinct Pathophysiological Trait in Obstructive Sleep Apnea.

Arousals from sleep vary in duration and intensity. Accordingly, the physiological consequences of different types of arousals may also vary. Factors that influence arousal intensity are only partly understood. This study aimed to determine if arousal intensity is mediated by the strength of the preceding respiratory stimulus, and investigate other factors mediating arousal intensity and its role on post-arousal ventilatory and pharyngeal muscle responses. Data were acquired in 71 adults (17 controls, 54 obstructive sleep apnea patients) instrumented with polysomnography equipment plus genioglossus and tensor palatini electromyography (EMG), a nasal mask and pneumotachograph, and an epiglottic pressure sensor. Transient reductions in CPAP were delivered during sleep to induce respiratory-related arousals. Arousal intensity was measured using a validated 10-point scale. Average arousal intensity was not related to the magnitude of the preceding respiratory stimuli but was positively associated with arousal duration, time to arousal, rate of change in epiglottic pressure and negatively with BMI (R2 > 0.10, P ≤ 0.006). High (> 5) intensity arousals caused greater ventilatory responses than low (≤ 5) intensity arousals (10.9 [6.8-14.5] vs. 7.8 [4.7-12.9] L/min; P = 0.036) and greater increases in tensor palatini EMG (10 [3-17] vs. 6 [2-11]%max; P = 0.031), with less pronounced increases in genioglossus EMG. Average arousal intensity is independent of the preceding respiratory stimulus. This is consistent with arousal intensity being a distinct trait. Respiratory and pharyngeal muscle responses increase with arousal intensity. Thus, patients with higher arousal intensities may be more prone to respiratory control instability. These findings are important for sleep apnea pathogenesis.

Model-based stability assessment of ventilatory control in overweight adolescents with obstructive sleep apnea during NREM sleep.

Obstructive sleep apnea (OSA) involves the interplay of several different factors such as an unfavorable upper airway anatomy, deficiencies in pharyngeal muscle responsiveness, a low arousal threshold, and ventilatory control instability. Although the stability of ventilatory control has been extensively studied in adults, little is known about its characteristics in the pediatric population. In this study, we developed a novel experimental setup that allowed us to perturb the respiratory system during natural non-rapid eye movement (NREM) sleep conditions by manipulating the inspiratory pressure, provided by a bilevel pressure ventilator, to induce sighs after upper airway stabilization. Furthermore, we present a modeling framework that utilizes the noninvasively measured ventilatory responses to the induced sighs and spontaneous breathing data to obtain representations of the processes involved in the chemical regulation of respiration and extract their stability characteristics. After validation with simulated data, the modeling technique was applied to data collected experimentally from 11 OSA and 15 non-OSA overweight adolescents. Statistical analysis of the model-derived stability parameters revealed a significantly higher plant gain and lower controller gain in the OSA group (P = 0.046 and P = 0.007, respectively); however, no differences were found in loop gain (LG) and circulatory time delay between the groups. OSA severity and LG, within the 0.03-0.04-Hz frequency band, were significantly negatively associated (r = -0.434, P = 0.026). Contrary to what has been found in adults, our results suggest that in overweight adolescents, OSA is unlikely to be initiated through ventilatory instability resulting from elevated chemical loop gain.

Recent advances in obstructive sleep apnea pathophysiology and treatment

Obstructive sleep apnea (OSA) is a sleep disorder characterized by recurring collapse of the pharyngeal airway leading to restricted airflow. OSA is becoming increasingly common with at least moderate disease now evident in 17% of middle aged men and 9% of women. The list of recognized adverse health consequences associated with OSA is growing and includes daytime symptoms of sleepiness, impaired cognition and risk of motor vehicle accidents as well as associations with hypertension, cardiovascular morbidity, malignancy and all-cause mortality. In this context adequate treatment of OSA is imperative; however, there are well-recognized pitfalls in the uptake and usage of the standard treatment modality, Continuous Positive Airway Pressure (CPAP). A broad range of pathophysiological mechanisms are now recognized beyond an anatomically smaller pharyngeal airway and impaired compensatory pharyngeal muscle responsiveness. Perturbations in ventilatory control stability, low arousal threshold, sleep-related decrease in lung volume and fluid redistribution as well as upper airway surface tension have all been shown to variously contribute to sleep-disordered breathing. Many new therapies are emerging from these advances in understanding of the mechanisms of OSA. Although many may not be universally effective, the promise of phenotyping patients according to their individual pathophysiology in order to target one or more therapies may prove highly effective and allow the treatment of OSA towards a personalized medicine approach.

Which OSA Patients Might Respond to Nasal Valves?

Which OSA Patients Might Respond to Nasal Valves?