O013 The pathogenesis of obstructive sleep apnea in individuals with comorbid insomnia and obstructive sleep apnoea (COMISA)

Abstract Obstructive sleep apnea (OSA) and Insomnia are prevalent sleep disorders which are highly comorbid. This frequent co-occurrence suggests a shared etiology may exist. OSA is caused by the interaction of four pathophysiological traits: a highly collapsible upper airway, elevated loop gain, a low arousal threshold, and poor muscle compensation. No study has ascertained whether these traits are influenced by insomnia. We aimed to quantify the four traits which contribute to OSA in individuals diagnosed with comorbid insomnia and OSA (COMISA). We non-invasively determined these traits in 52 COMISA patients (Age: 56±14 years) with mild-to-severe OSA (AHI=21.2±10.63 events/h) using polysomnography. Our results indicated that 83% of COMISA patients had a low arousal threshold and only 2% of patients exhibited a highly collapsible airway using previously defined thresholds. Multiple linear regression revealed the arousal threshold (b=0.24, 95%CI[0.11, 0.37], β=0.47, p<0.001) and loop gain (b=23.6, 95%CI[7.02, 40.18], β=0.33, p<0.01) were the strongest predictors of OSA severity in our sample. There was no significant relationship between the arousal threshold and insomnia severity measured by the insomnia severity index (ISI). Further work is being performed to compare these findings with a matched sample of OSA only participants. Our preliminary findings demonstrate OSA in COMISA is characterized by a mildly collapsible airway/low arousal threshold phenotype and is largely driven by non-anatomical factors including a low arousal threshold and high loop gain. OSA treatments which are effective in patients with mild anatomical compromise and raise the arousal threshold may provide therapeutic benefit in COMISA patients.

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Targeting Endotypic Traits with Medications for the Pharmacological Treatment of Obstructive Sleep Apnea. A Review of the Current Literature

Journal of Clinical Medicine ◽

10.3390/jcm8111846 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1846 ◽

Cited By ~ 7

Author(s):

Taranto-Montemurro ◽

Messineo ◽

Wellman

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Muscle Activity ◽

Upper Airway ◽

Loop Gain ◽

Arousal Threshold ◽

The Past ◽

Obstructive Sleep ◽

Near Future ◽

Made In

Obstructive sleep apnea (OSA) is a highly prevalent condition with few therapeutic options. To date there is no approved pharmacotherapy for this disorder, but several attempts have been made in the past and are currently ongoing to find one. The recent identification of multiple endotypes underlying this disorder has oriented the pharmacological research towards tailored therapies targeting specific pathophysiological traits that contribute differently to cause OSA in each patient. In this review we retrospectively analyze the literature on OSA pharmacotherapy dividing the medications tested on the basis of the four main endotypes: anatomy, upper airway muscle activity, arousal threshold and ventilatory instability (loop gain). We show how recently introduced drugs for weight loss that modify upper airway anatomy may play an important role in the management of OSA in the near future, and promising results have been obtained with drugs that increase upper airway muscle activity during sleep and reduce loop gain. The lack of a medication that can effectively increase the arousal threshold makes this strategy less encouraging, although recent studies have shown that the use of certain sedatives do not worsen OSA severity and could actually improve patients’ sleep quality.

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Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity

Journal of Applied Physiology ◽

10.1152/japplphysiol.01074.2020 ◽

2021 ◽

Author(s):

Atqiya Aishah ◽

Richard Lim ◽

Scott A. Sands ◽

Luigi Taranto-Montemurro ◽

Andrew Wellman ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Loop Gain ◽

Double Blind ◽

Receptor Selectivity ◽

Arousal Threshold ◽

Solifenacin Succinate ◽

Obstructive Sleep ◽

Airway Physiology

The combination of the noradrenergic agent atomoxetine plus the anti-muscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different anti-muscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different anti-muscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology.10 people with predominantly severe OSA completed a double-blind, randomised, placebo-controlled, cross-over trial. Participants completed 3 overnight in-laboratory sleep studies after either 80mg atomoxetine+5mg solifenacin succinate (ato-sol) or 80mg atomoxetine+2mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next day subjective sleepiness (Karolinska Sleepiness Scale:KSS) and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnoea index versus placebo (p=0.63). Ato-sol caused a shift towards milder respiratory events with reduced frequency of obstructive apneas (13±14vs. 22±17events/h; mean±SD, p=0.04) and increased hypopneas during NREM (38±21vs. 24±18events/h, p=0.006) with improved nadir oxygenation versus placebo (83±4vs. 80±8%, p=0.03). Both combinations reduced loop gain by ~10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS=4.3±2.2vs. 5.6±1.6, p=0.03).Atomoxetine+biperiden hydrochloride reduces perceived sleepiness and atomoxetine+solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine+oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and anti-muscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.

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O001 Reboxetine reduces obstructive sleep apnea severity: a randomized trial

SLEEP Advances ◽

10.1093/sleepadvances/zpab014.000 ◽

2021 ◽

Vol 2 (Supplement_1) ◽

pp. A1-A1

Author(s):

T Altree ◽

A Aishah ◽

K Loffler ◽

R Grunstein ◽

D Eckert

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Respiratory Control ◽

Upper Airway ◽

Apnea Hypopnea Index ◽

Loop Gain ◽

Double Blind ◽

Obstructive Sleep ◽

High Loop ◽

Control Stability

Abstract Introduction Noradrenergic and muscarinic processes are crucial for pharyngeal muscle control during sleep. Selective norepinephrine reuptake inhibitors (SNRIs) such as reboxetine combined with an antimuscarinic reduce obstructive sleep apnea (OSA) severity. The effects of reboxetine alone on OSA severity are unknown. Methods Double-blind, placebo-controlled, three-way crossover trial in 16 people with OSA. Each participant completed three overnight polysomnograms (~1-week washout). Single doses of reboxetine 4mg, placebo, or reboxetine+oxybutynin 5mg were administered before sleep (randomized order). The primary outcome was apnea-hypopnea index (AHI). Secondary outcomes included other polysomnography parameters, next day sleepiness and alertness. Endotyping analysis was performed to determine the medications’ effects on OSA pathophysiological mechanisms. Results Reboxetine reduced the AHI by 5.4 [95% CI -10.4 to -0.3] events/h, P=0.03 (men: -24±27%; women: -0.7±32%). The addition of oxybutynin did not further reduce AHI. Reboxetine alone and reboxetine+oxybutynin reduced overnight hypoxemia versus placebo (e.g. 4% oxygen desaturation index 10.4±12.8 vs. 10.6±12.8 vs. 15.7±14.7 events/h, P=0.02). Mechanistically, reboxetine and reboxetine+oxybutynin improved pharyngeal collapsibility and respiratory control stability. Men had higher baseline loop gain. Larger reductions in AHI with reboxetine occurred in those with high loop gain. Neither drug intervention changed next day sleepiness or alertness. Discussion A single 4mg dose of reboxetine modestly reduces OSA severity without further improvement with the addition of an antimuscarinic. Reboxetine increases breathing stability via improvements in pharyngeal collapsibility and respiratory control. These findings provide new insight into the role of SNRIs on upper airway stability during sleep and have important implications for pharmacotherapy development for OSA.

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Pathophysiology of Obstructive Sleep Apnea in Aging Women

Current Sleep Medicine Reports ◽

10.1007/s40675-021-00218-x ◽

2021 ◽

Author(s):

Qingchao Qiu ◽

Jason H. Mateika

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Upper Airway ◽

Loop Gain ◽

Younger Women ◽

Arousal Threshold ◽

Obstructive Sleep ◽

Aging Women ◽

Long Term Facilitation

AbstractThe following review is designed to explore the pathophysiology of sleep apnea in aging women. The review initially introduces four endotypes (i.e., a more collapsible airway, upper airway muscle responsiveness, arousal threshold, and loop gain) that may have a role in the initiation of obstructive sleep apnea. Thereafter, sex differences in the prevalence of sleep apnea are considered along with differences in the prevalence that exist between younger and older women. Following this discussion, we consider how each endotype might contribute to the increase in prevalence of sleep apnea in aging women. Lastly, we address how modifications in one form of respiratory plasticity, long-term facilitation, that might serve to mitigate apneic events in younger women may be modified in aging women with obstructive sleep apnea. Overall, the published literature indicates that the prevalence of sleep apnea is increased in aging women. This increase is linked primarily to a more collapsible airway and possibly to reduced responsiveness of upper airway muscle activity. In contrast, modifications in loop gain or the arousal threshold do not appear to have a role in the increased prevalence of sleep apnea in aging women. Moreover, we suggest that mitigation of long-term facilitation could contribute to the increased prevalence of sleep apnea in aging women.

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0710 Hypoglossal Neurostimulation In Rem- Vs. Nrem-predominant Obstructive Sleep Apnea

SLEEP ◽

10.1093/sleep/zsaa056.706 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A270-A270

Author(s):

C I Cabrera ◽

B Szelestey ◽

K Strohl ◽

A Schell

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Univariate Analysis ◽

Disease Process ◽

Loop Gain ◽

Upper Airway Stimulation ◽

Arousal Threshold ◽

Obstructive Sleep ◽

Baseline Characteristics ◽

Star Trial

Abstract Introduction Obstructive sleep apnea (OSA) is a chronic condition that requires appropriate treatment strategies to optimize outcomes while minimizing risk. In addition to anatomy, physiologic factors such as arousal threshold and loop gain (i.e. “endotypes”) play a known role in the disease process. Because loop gain tends to be higher and arousal threshold lower in NREM sleep, we hypothesize that patients with NREM-predominance may achieve less success with anatomical therapy such as upper airway stimulation (UAS). Our study aims to evaluate baseline characteristics and objective results related to NREM-predominance in patients treated with UAS. Methods Using data from the STAR trial, we identified patients (n=103) with at least 20 minutes of REM on baseline testing and complete demographic and disease data at baseline and month 18. Baseline NREM-predominant disease (percent NREM events > 50) was defined as a binary variable. We created two cohorts: 1) patients with REM-predominant disease and 2) those with NREM-predominant disease. ODI and AHI were evaluated at month 18. Results Overall 62% (n=64) of patients had NREM-predominant disease at baseline. Other baseline characteristics were similar between both groups. In univariate analysis, age was significantly associated with lower AHI in the NREM-predominant population (p<0.05) but not in the REM-predominant group (p>0.05). Results were similar for ODI. For both groups, increasing age was correlated negatively with increasing AHI; this correlation was stronger in the NREM-predominant group Conclusion A majority of patients in the STAR trial had NREM-predominant OSA at baseline. There appears to be an interaction between NREM-predominance and age as predictors of UAS outcomes. Support

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Variations in loop gain and arousal threshold during NREM sleep are affected by time of day over a 24-hour period in participants with obstructive sleep apnea

Journal of Applied Physiology ◽

10.1152/japplphysiol.00376.2020 ◽

2020 ◽

Vol 129 (4) ◽

pp. 800-809

Author(s):

Shipra Puri ◽

Mohamad El-Chami ◽

David Shaheen ◽

Blake Ivers ◽

Gino S. Panza ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Nrem Sleep ◽

Time Of Day ◽

Loop Gain ◽

Arousal Threshold ◽

Obstructive Sleep ◽

Critical Closing Pressure ◽

Chemoreflex Sensitivity ◽

Closing Pressure

Loop gain and the arousal threshold during non-rapid eye movement (NREM) sleep are greater in the morning compared with the afternoon and evening. Loop gain measures are correlated to chemoreflex sensitivity and the critical closing pressure measured during NREM sleep in the evening, morning, and afternoon. Breathing (in)stability and efficaciousness of treatments for obstructive sleep apnea may be modulated by a circadian rhythmicity in loop gain and the arousal threshold.

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Arousal and ventilatory responses during sleep in children with obstructive sleep apnea

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.6.1926 ◽

1998 ◽

Vol 84 (6) ◽

pp. 1926-1936 ◽

Cited By ~ 93

Author(s):

Carole L. Marcus ◽

Janita Lutz ◽

John L. Carroll ◽

Owen Bamford

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Sleep Apnea Syndrome ◽

Upper Airway ◽

Respiratory Drive ◽

Ventilatory Control ◽

Arousal Threshold ◽

Ventilatory Responses ◽

Obstructive Sleep ◽

Upper Airway Muscles

Abnormal central regulation of upper airway muscles may contribute to the pathophysiology of the childhood obstructive sleep apnea syndrome (OSAS). We hypothesized that this was secondary to global abnormalities of ventilatory control during sleep. We therefore compared the response to chemical stimuli during sleep between prepubertal children with OSAS and controls. Patients with OSAS aroused at a higher[Formula: see text] (58 ± 2 vs. 60 ± 5 Torr, P < 0.05); those with the highest apnea index had the highest arousal threshold ( r = 0.52, P < 0.05). The hypercapnic arousal threshold decreased after treatment. For all subjects, hypoxia was a poor stimulus to arousal, whereas hypercapnia and, particularly, hypoxic hypercapnia were potent stimuli to arousal. Hypercapnia resulted in decreased airway obstruction in OSAS. Ventilatory responses were similar between patients with OSAS and controls; however, the sample size was small. We conclude that children with OSAS have slightly blunted arousal responses to hypercapnia. However, the overall ventilatory and arousal responses are normal in children with OSAS, indicating that a global deficit in respiratory drive is not a major factor in the etiology of childhood OSAS. Nevertheless, subtle abnormalities in ventilatory control may exist.

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Cognitive and behavioral therapy for insomnia increases the use of continuous positive airway pressure therapy in obstructive sleep apnea participants with comorbid insomnia: a randomized clinical trial

SLEEP ◽

10.1093/sleep/zsz178 ◽

2019 ◽

Vol 42 (12) ◽

Cited By ~ 17

Author(s):

Alexander Sweetman ◽

Leon Lack ◽

Peter G Catcheside ◽

Nick A Antic ◽

Simon Smith ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Positive Airway Pressure ◽

Behavioral Therapy ◽

Comorbid Insomnia ◽

Group Outcomes ◽

Obstructive Sleep ◽

Cognitive And Behavioral Therapy ◽

Insomnia Symptoms ◽

Insomnia Severity

Abstract Study Objectives Insomnia and obstructive sleep apnea (OSA) commonly co-occur which makes OSA difficult to treat with continuous positive airway pressure (CPAP). We conducted a randomized controlled trial in participants with OSA and co-occurring insomnia to test the hypothesis that initial treatment with cognitive and behavioral therapy for insomnia (CBT-i), versus treatment as usual (TAU) would improve insomnia symptoms and increase subsequent acceptance and use of CPAP. Methods One hundred and forty-five participants with OSA (apnea-hypopnea index ≥ 15) and comorbid insomnia were randomized to either four sessions of CBT-i, or TAU, before commencing CPAP therapy until 6 months post-randomization. Primary between-group outcomes included objective average CPAP adherence and changes in objective sleep efficiency by 6 months. Secondary between-group outcomes included rates of immediate CPAP acceptance/rejection, and changes in; sleep parameters, insomnia severity, and daytime impairments by 6 months. Results Compared to TAU, participants in the CBT-i group had 61 min greater average nightly adherence to CPAP (95% confidence interval [CI] = 9 to 113; p = 0.023, d = 0.38) and higher initial CPAP treatment acceptance (99% vs. 89%; p = 0.034). The CBT-i group showed greater improvement of global insomnia severity, and dysfunctional sleep-related cognitions by 6 months (both: p < 0.001), and greater improvement in sleep impairment measures immediately following CBT-i. There were no between-group differences in sleep outcomes, or daytime impairments by 6 months. Conclusions In OSA participants with comorbid insomnia, CBT-i prior to initiating CPAP treatment improves CPAP use and insomnia symptoms compared to commencing CPAP without CBT-i. OSA patients should be evaluated for co-occurring insomnia and considered for CBT-i before commencing CPAP therapy. Clinical Trial Treating comorbid insomnia with obstructive sleep apnea (COMSIA) study: A new treatment strategy for patients with combined insomnia and sleep apnea, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365184 Australian New Zealand Clinical Trials Registry: ACTRN12613001178730. Universal Trial Number: U1111-1149-4230.

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