Respiratory Arousal Threshold Research Articles

P019 Obstructive sleep apnoea endotypes in people with multiple sclerosis

Abstract Purpose Obstructive sleep apnoea (OSA) is common in people with multiple sclerosis (MS) despite a lack of typical risk factors for OSA in people with MS such as obesity and male predominance. Therefore, underlying factors other than sex and obesity may be particularly important in the pathogenesis of OSA in people with MS. Thus, the primary aim of this study was to determine the relative contributions of OSA endotypes in people with MS and compare this to matched controls with OSA only. Methods Eleven people with MS and OSA (MS-OSA group) (apnoea-hypopnoea index [AHI]>5events/h) and eleven controls matched for OSA severity, age and sex without MS (OSA group) were studied. Participants underwent a detailed overnight polysomnography with an epiglottic pressure catheter and genioglossus intramuscular electrodes to allow for quantification of pathophysiological contributors to OSA. This included the respiratory arousal threshold, genioglossus muscle responsiveness, respiratory loop gain and upper airway collapsibility. Results Measures of the four primary OSA endotypes were not different between the MS-OSA and OSA groups (e.g. NREM respiratory arousal threshold -27±15 vs. -23±8 cmH2O respectively, p=0.24). Within group analysis indicated higher loop gain in non-obese MS-OSA participants compared to obese MS-OSA participants (0.53±0.11 vs. 0.37±0.11, p=0.04). Conclusions Overall, OSA endotypes are similar between MS-OSA participants and matched OSA controls. However, within the MS-OSA group, non-obese participants have higher loop gain (unstable respiratory control) compared to obese participants. Thus, unstable respiratory control may play an important role in OSA pathogenesis in many people with MS.

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.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p=0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p=0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

Vulnerability to Postoperative Complications in Obstructive Sleep Apnea: Importance of Phenotypes.

Obstructive sleep apnea (OSA) is a common comorbidity in patients undergoing surgical procedures. Patients with OSA are at heightened risk of postoperative complications. Current treatments for OSA focus on alleviating upper airway collapse due to impaired upper airway anatomy. Although impaired upper airway anatomy is the primary cause of OSA, the pathogenesis of OSA is highly variable from person to person. In many patients, nonanatomical traits play a critical role in the development of OSA. There are 4 key traits or "phenotypes" that contribute to OSA pathogenesis. In addition to (1) impaired upper airway anatomy, nonanatomical contributors include: (2) impaired upper airway dilator muscle responsiveness; (3) low respiratory arousal threshold (waking up too easily to minor airway narrowing); and (4) unstable control of breathing (high loop gain). Each of these phenotypes respond differently to postoperative factors, such as opioid medications. An understanding of these phenotypes and their highly varied interactions with postoperative risk factors is key to providing safer personalized care for postoperative patients with OSA. Accordingly, this review describes the 4 OSA phenotypes, highlights how the impact on OSA severity from postoperative risk factors, such as opioids and other sedatives, is influenced by OSA phenotypes, and outlines how this knowledge can be applied to provide individualized care to minimize postoperative risk in surgical patients with OSA.

Low Arousal Threshold: A Potential Bridge Between OSA and Periodic Limb Movements of Sleep.

ObjectivePeriodic Limb Movements of Sleep (PLMS) is a poorly understood comorbidity with close association to Obstructive Sleep Apnea (OSA). The mechanistic link between the two is unclear. Recent studies on the latter have uncovered low respiratory arousal threshold as an important non-anatomical cause of the disorder. This study sought to investigate whether periodic limb movements are associated with the low respiratory arousal threshold (ArTH) in OSA.MethodsRetrospective data on 720 OSA patients (mean age = 47.0) who underwent Polysomnography (PSG) were collected. Using PLMS diagnostic criteria of PLMS index ≥ 15, patients were divided into the OSA-PLMS group (n=95) and the OSA-only group (n=625). Binary logistic regression analysis was used to examine the correlation between PLMS and the presence of low ArTH, classified using a predicted tool (developed by Edward et al) requiring meeting at least two of the three criteria: apnea-hypopnea index (AHI) < 30/h, nadir oxygen saturation (SaO2) > 82.5%, and fraction of hypopneas > 58.3%. The resulting model was validated in the external MrOS database.ResultsThe patients in the OSA-PLMS group tend to be older, with a higher prevalence of hypertension, diabetes, and stroke. PLMS was associated with age, diabetes, oxygen desaturation index, and low respiratory arousal threshold (OR=8.78 (4.73–16.30), p<0.001). When validated against the MrOS database, low ArTH remained a significant predictor of PLMS with an odds ratio of 1.33 (1.08–1.64, p = 0.009).ConclusionThis is the first study that demonstrated a strong correlation between PLMS and low respiratory arousal threshold. This suggests a possible mechanistic link between the physical manifestation of PLMS and the non-anatomical low arousal threshold phenotype in OSA.

Standardized framework to report on the role of sleeping position in sleep apnea patients.

Sleep apnea is a multifactorial illness which can be differentiated in various physiological phenotypes as a result of both anatomical and non-anatomical contributors (e.g., low respiratory arousal threshold, high loop gain). In addition, the frequency and duration of apneas, in the majority of patients with OSA, are influenced by sleeping position. Differences in characteristics between non-positional patients (NPP) and positional patients (PP) suggest another crucial phenotype distinction, a clinical phenotype focusing on the role of sleeping position on sleep apnea. Since this clinical phenotype distinction has therapeutic implications, further research is necessary to better understand the pathophysiology behind this phenotypic trait and to improve management of PP. Therefore, we suggest a standardized framework that emphasizes the role of sleeping position when reporting clinical and research data on sleep apnea. We identified 5 key topics whereby a standardized framework to report on the role of sleeping position would be of added value: (1) sleep study data, (2) anatomical, morphological and physiological factors, (3) drug-induced sleep endoscopy (DISE) findings, (4) sleep apnea management, and (5) effectiveness versus efficacy of positional therapy in sleep apnea management. We performed a literature search to identify evidence to describe and support the rationale behind these5 main recommendations. In this paper, we present the rationale behind this constructand present specific recommendations such as reporting sleep study indices (disease severity) and sleep time spent in various sleeping positions. The same is suggested for DISE findings and effect of treatment. Sleep study indices (disease severity), anatomical, morphological, and physiological factors in sleep apnea patientsshould be reported separately for PP and NPP. Applying these suggestions in future research will improve patient care, assist in better understanding of this dominant phenotype, and will enhance accurate comparisons across studies and future investigations.

Clinical characteristics of Asian patients withsleep apnea with low arousal threshold and sleep structure change with continuous positive airway pressure.

Low respiratory arousal threshold (ArTH) has been observed to be prevalent in patients withobstructive sleep apnea (OSA), and is associated with poor adherence to continuous positive airway pressure (CPAP) treatment. This study aimed to examine the associations between low ArTH and clinical characteristics. The second aim was to examine sleep structure changes between diagnostic polysomnography (PSG) and CPAP titration studies. PSG data for 3718 adults who had an apnea-hypopnea index (AHI) ≥ 5 were reviewed retrospectively, as well as 206 CPAP titration studies among these participants. Participants were dichotomized into low- and high-ArTH groups according to their PSG parameters. The associations between low ArTH and clinical characteristics were examined by multivariate logistic regressions. The sleep structure changes between PSG and CPAP titration studies were examined by repeated measures ANOVA. Fifty percent of patients withOSA had low ArTH. Compared with high-ArTH patients, low-ArTH patients were less obese and composed of a higher percentage of women. In logistic regression models, low ArTH was associated with bruxism and nocturia, but not with illnesses after adjusting for AHI and body mass index. Compared with diagnostic PSG studies, low-ArTH patients had significantly decreased stage changes and increased percentage of rapid eye movement sleep during CPAP titration studies. Low ArTH was prevalent in this large sample of patients withOSA. Arousal threshold was not associated with an increased risk of physical illnesses but was with certain clinical complaints. Low-ArTH patients benefited from CPAP titration study for improved sleep structure.

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.

Concomitant benzodiazepine and opioids decrease sleep apnoea risk in chronic pain patients.

BackgroundThe concurrent use of sedating centrally acting drugs and opioids by chronic pain patients occurs routinely despite concerns of negative impacts on respiration during sleep. The effects of centrally acting drugs and opioids on sleep apnoea have not been well characterised. The objective of this study was to assess the effect of concomitant centrally acting drugs and opioids on the prevalence and severity of sleep apnoea in chronic pain patients.MethodsWe conducted a prospective cohort study at five chronic pain clinics. Each participant underwent an in-laboratory polysomnography and daily morphine milligram equivalents were calculated. Participants were grouped into centrally acting drugs and opioid users versus sole opioid users.ResultsOf the 332 consented participants, 204 underwent polysomnography and 120 (58.8%) had sleep apnoea (72% obstructive, 20% central, and 8% indeterminate sleep apnoea). Overall, 35% (71 of 204) were taking opioids alone, and 65% (133 of 204) were taking centrally acting drugs and opioids. There was a 69% decrease in the odds of having sleep apnoea (apnoea–hypopnoea index ≥5 events·h−1) in participants taking benzodiazepine/opioids versus sole opioid users (OR 0.31, 95% CI:0.12–0.80, p=0.015). Additionally, concomitant benzodiazepine/opioids versus sole opioid use was associated with a decrease in respiratory arousal index scores (p=0.03). Mean overnight SpO2 was approximately 1% lower in the concomitant benzodiazepine/opioids group versus sole opioid users (93.1±2.5 versus 94.4±2.1%, p=0.01).ConclusionIn chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.

Low Respiratory Arousal Threshold (LRAT) in African Americans with Obstructive Sleep Apnea (OSA). (2740)

Low Respiratory Arousal Threshold (LRAT) in African Americans with Obstructive Sleep Apnea (OSA). (2740)

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.

Is catathrenia sleep related breathing disorders? - PSG findings and respiratory arousal threshold

Is catathrenia sleep related breathing disorders? - PSG findings and respiratory arousal threshold

High dose zopiclone does not change OSA severity, the respiratory arousal threshold, genioglossus muscle responsiveness or next-day sleepiness and alertness in selected people with OSA

High dose zopiclone does not change OSA severity, the respiratory arousal threshold, genioglossus muscle responsiveness or next-day sleepiness and alertness in selected people with OSA

Wake-up stroke is associated with decreased percentage of individuals with low respiratory arousal threshold

Wake-up stroke is associated with decreased percentage of individuals with low respiratory arousal threshold

Lung air trapping lowers respiratory arousal threshold and contributes to sleep apnea pathogenesis in COPD patients with overlap syndrome

Study objectivesOverlap syndrome occurs when obstructive sleep apnea (OSA) and chronic obstructive pulmonary disorder (COPD) coexist in the same patient. Although several studies highlighted the importance of clinical phenotyping in OSA, the trait contribution to OSA pathogenesis in overlap syndrome has not been investigated. With this pilot study, we aimed to measure OSA determinants and their relationship with functional respiratory parameters in a sample of patients with overlap syndrome. In particular, we hypothesize that patients with COPD have in the low arousal threshold a major contributor for the development of OSA. MethodsTen consecutive non-hypercapnic COPD patients (body mass index<35 kg/m2) suffering from overlap syndrome with no other relevant comorbidities underwent a phenotyping polysomnography. Traits were measured with CPAP dial-downs. ResultsArousal threshold was found to be inversely associated to functional measures of lung air trapping and static hyperinflation. Particularly, correlations with residual volume (r2 = 0.49, p = 0.024) and residual volume to total lung capacity ratio (r2 = 0.48, p = 0.026) were evident. Only 20% of patients showed a high upper airway passive collapsibility as single pathological trait. In contrast, among those patients with multiple altered traits (6 out of 10), all had an elevated loop gain and 4 (∼65%) a low arousal threshold. ConclusionsHigh loop gain and particularly low arousal threshold seem important contributors to OSA pathogenesis and severity in patients with COPD. Recognizing in COPD patients these features as key traits may open avenues for personalized medicine in the field of overlap syndrome.

Reduced cortical arousability to nocturnal apneic episodes in patients with wake-up ischemic stroke

Study objectivesSleep breathing disorders (SBD) have been linked to wake-up stroke (WUS). Respiratory arousals have an important role in responding to danger during sleep, yet currently no studies have investigated respiratory arousability in WUS. In this study, we used a clinical tool to predict low respiratory arousal threshold (ArTH), and then compared respiratory arousability in patients with WUS and non-WUS. MethodsWe enrolled 119 patients with acute ischemic stroke and assigned them into WUS (n = 34) and non-WUS (n = 85) groups. All participants underwent polysomnography (PSG) during the acute phase of stroke. The respiratory ArTH predictive tool assigns one point for each of the following: apnea-hypopnea index (AHI) < 30/h, nadir oxygen saturation (SaO2) > 82.5%, and fraction of hypopneas > 58.3%. An ArTH score ≥2 represents low respiratory ArTH. ResultsOur results reconfirmed the association between moderate-to-severe sleep apnea syndrome and WUS (OR 2.879, 95% CI 1.17–7.089, p = 0.021). Significantly fewer participants with obstructive sleep apnea (AHI ≥ 5/h) had low respiratory ArTH in the WUS group than in the non-WUS group (34.8% vs. 68.1%, respectively, p = 0.008). High respiratory ArTH was independently associated with WUS (OR 5.556, 95% CI 1.959–15.761, p = 0.001). ConclusionsThe correlation between SBD and WUS suggests that sleep apnea might induce acute physiological changes that trigger the onset of stroke. We show that reduced respiratory arousability is associated with WUS, and hypothesize that reduced cortical capability to generate respiratory arousal may have a role in triggering stroke during sleep.

Is there a threshold that triggers cortical arousals in obstructive sleep apnea.

To determine whether there is a consistent epiglottic pressure value that predicts respiratory arousal from sleep. Thirty-one patients with obstructive sleep apnea underwent overnight polysomnography while instrumented with an epiglottic catheter to measure airway pressures. Nadir epiglottic pressures during respiration events (obstructive apneas/hypopneas) terminated with or without arousals were compared. The events were selected by two methods, (1) 20 events with/without arousals were randomly selected, and (2) Events were sampled in pairs (one terminated with arousal and one without arousal) to minimize the effect of sleep duration/stage on the measurement. A total of 1,317 respiratory events were analyzed. There was substantial variability in nadir epiglottic pressure within an individual and among different individuals. The average pressure of 20 randomly selected events with arousals was (-21.2 ± 11.2, ranged -6.68 to -63.34 cm H2O). The nadir epiglottic pressure during respiratory events in NREM stage 2 sleep terminated with arousals was more negative compared with those terminated without arousals using both sampling methods (-23.5 vs. -18.5 cm H2O, p = 0.007 and -20.3 vs. -16.3 cm H2O, p < 0.001). There were very different levels of epiglottic pressures that preceded arousals within and among individuals. However, cortical arousals are associated with a level of more negative epiglottic pressure compared to events terminated without arousal, findings which support the concept of a respiratory arousal threshold. The study used existing data to study methodology (from clinical trial "The Impact of Arousal Threshold in Obstructive Sleep Apnea" https://clinicaltrials.gov/show/NCT02264353) and it is not a clinical trial.

Prevalence, Associated Clinical Features, and Impact on Continuous Positive Airway Pressure Use of a Low Respiratory Arousal Threshold Among Male United States Veterans With Obstructive Sleep Apnea.

Determine the prevalence of, and clinical features associated with, a low respiratory arousal threshold (ArTH) among patients with obstructive sleep apnea (OSA), and to assess whether a low ArTH is associated with reduced long-term CPAP use. Cross-sectional and longitudinal analyses were performed in an observational study conducted among 940 male Veterans with OSA. Data for clinical characteristics, polysomnography characteristics, and long-term (5 ± 2 years) CPAP use were obtained from clinical records. Logistic regression was used to assess the associations between low ArTH and clinical features, including regular CPAP use. A low ArTH was observed in 38% of participants overall, and was more common among nonobese (body mass index < 30 kg/m2) patients (55%). In adjusted analyses, increasing body mass index (per 5 kg/m2) and antihypertensive medication use were negatively associated with low ArTH, with odds ratio (OR) (95% confidence interval [CI]) of 0.77 (0.69, 0.87) and 0.69 (0.49, 0.98), respectively. Conversely, increasing age (per 10 years) and antidepressant use-OR (95% CI) 1.15 (1.01,1.31) and 1.54 (1.14,1.98), respectively-were positively associated with low ArTH. Nonobese patients with low ArTH were less likely to be regular CPAP users-OR (95% CI) 0.38 (0.20, 0.72)-in an adjusted model. Low ArTH is a common trait among Veterans with OSA and is more frequent among those who are older and nonobese and those taking antidepressants, but is less frequent among patients taking antihypertensive medications. A marked reduction of long-term CPAP use in nonobese patients with low ArTH highlights the importance of understanding a patient's physiologic phenotype for OSA management, and suggests potential targets to improve CPAP adherence. A commentary on this article appears in this issue on page 713.

Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem.

Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data are lacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousal threshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep.21 individuals with and without OSA (18-65 years) completed 84 detailed sleep studies after receiving temazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind, placebo-controlled, crossover trial (ACTRN12612001004853).The arousal threshold increased with zolpidem and zopiclone versus placebo (mean±sd -18.3±10 and -19.1±9 versus -14.6±7 cmH2O; p=0.02 and p<0.001) but not with temazepam (-16.8±9 cmH2O; p=0.17). Genioglossus muscle activity during stable non-REM sleep and responsiveness during airway narrowing was not different with temazepam and zopiclone versus placebo but, paradoxically, zolpidem increased median muscle responsiveness three-fold during airway narrowing (median -0.15 (interquartile range -1.01 to -0.04) versus -0.05 (-0.29 to -0.03)% maximum EMG per cmH2O epiglottic pressure; p=0.03). The upper airway critical closing pressure did not change with any of the hypnotics.These doses of common hypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airway muscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airway narrowing with zolpidem.

Obstructive Sleep Apnea without Obesity Is Common and Difficult to Treat: Evidence for a Distinct Pathophysiological Phenotype.

To determine the proportion and physiological characteristics of nonobese patients with obstructive sleep apnea (OSA) and their response to prescribed therapy. Data from 163 consecutive in-laboratory diagnostic sleep studies for participants referred to an academic teaching-hospital sleep clinic for suspected OSA were assessed. Sleep and anthropometric parameters at baseline and follow-up (up to 22 mo) were examined and compared between obese and nonobese patients with a diagnosis of OSA (apnea-hypopnea index > 5 events/h sleep). A key nonanatomical contributor to OSA pathogenesis, the respiratory arousal threshold, was compared between groups. Twenty-five percent of the participants with a diagnosis of OSA had a body mass index (BMI) within the normal range (BMI < 25 kg/m2) and 54% had a BMI < 30 kg/m2 (nonobese). Of the patients prescribed continuous positive airway pressure (CPAP), more nonobese patients reported not using their CPAP machine at all at follow-up (36% vs. 13%, p = 0.03). Objective CPAP compliance was also lower in the nonobese patients with OSA (5.1 ± 0.4 vs. 6.4 ± 0.4 h/night, p < 0.03). A higher proportion of the nonobese patients had a low respiratory arousal threshold compared to obese OSA patients (86% vs. 60%, p < 0.001). A substantial proportion of patients with OSA are not obese. These patients are challenging to treat with existing therapies as they are less adherent and compliant with CPAP therapy. Nonanatomical contributors to OSA, such a low threshold for arousal, are likely to be particularly important in OSA pathogenesis in nonobese patients with OSA. These findings have important implications for the pathogenesis of OSA in nonobese patients and potential therapeutic targets for this group of patients.