Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

RATIONALE: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone. METHODS: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index. RESULTS: Although AtoOxy lowered AHI by 49 (33, 62)%baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)%baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)%baseline, primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)%baseline) and acetazolamide (+37 (5, 58)%baseline), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)%baseline). Arousal index was also modestly reduced with each intervention (11%baseline-16%baseline). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy. CONCLUSIONS: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms. TRIAL REGISTRATION NUMBER: NCT03892772.

A review of supine position related obstructive sleep apnea: Classification, epidemiology, pathogenesis and treatment.

Supine related obstructive sleep apnea (OSA) is the most common clinical and physiological phenotype of OSA. This condition is recognizable by patients, their families and through polysomnographic recordings. Commonly used definitions distinguish the presence of supine related OSA when respiratory events occur at twice the frequency when the patient lies in the supine compared to non-supine sleeping positions. Recent physiology studies have demonstrated that airway obstruction arises more commonly in the supine position particularly at the level of the soft palate and epiglottis. Increased airway collapsibility is reliability observed supine relative to lateral position. To a lesser extent, changes in control of breathing favour less stable ventilation when the supine sleeping posture is adopted. Many treatments have been developed and trialled to help patients avoid sleeping on their back. The last 10 years has seen the emergence of vibrotactile warning devices that are worn on the patients' neck or chest. High quality randomized controlled trial data is accumulating on the efficacy and common pitfalls of the application of these treatments.

Obstructive Sleep Apnea Is a Distinct Physiological Endotype in Individuals with Comorbid Insomnia and Sleep Apnea.

Rationale: With up to 40% of individuals with either insomnia or obstructive sleep apnea (OSA) demonstrating clinically significant symptoms of the other disorder, the high degree of comorbidity among the two most common sleep disorders suggests a bidirectional relationship and/or shared underpinnings. Although the presence of insomnia disorder is believed to influence the underlying pathophysiology of OSA, this influence is yet to be examined directly. Objectives: To investigate whether the four OSA endotypes (upper airway collapsibility, muscle compensation, loop gain, and the arousal threshold) are different in patients with OSA with and without comorbid insomnia disorder. Methods: Using the ventilatory flow pattern captured from routine polysomnography, the four OSA endotypes were measured in 34 patients with OSA who met the diagnostic criteria for insomnia disorder (COMISA) and 34 patients with OSA without insomnia (OSA only). Patients demonstrated mild-to-severe OSA (apnea-hypopnea index, 25.8 ± 2.0 events/h) and were individually matched according to age (50.2 ± 1.5 yr), sex (42 male: 26 female), and body mass index (29.3 ± 0.6 kg/m2). Results: Compared with patients with OSA without comorbid insomnia, patients with COMISA demonstrated significantly lower respiratory arousal thresholds (128.9 [118.1 to 137.1] vs. 147.7 [132.3 to 165.0] % eupneic ventilation ([Formula: see text]); U = 261; 95% confidence interval [CI], -38.3 to -13.9; d = 1.1; P < 0.001), less collapsible upper airways (88.2 [85.5 to 94.6] vs. 72.9 [64.7 to 79.2] %[Formula: see text]; U = 1081; 95% CI, 14.0 to 26.7; d = 2.3; P < 0.001), and more stable ventilatory control (i.e., lower loop gain: 0.51 [0.44 to 0.56] vs. 0.58 [0.49 to 0.70]; U = 402; 95% CI, -0.2 to -0.01; d = 0.05; P = 0.03). Muscle compensation was similar between groups. Moderated linear regression revealed that the arousal threshold moderated the relationship between collapsibility and OSA severity in patients with COMISA but not in patients with OSA only. Conclusions: A low arousal threshold is an overrepresented endotypic trait in individuals with COMISA and may exhibit a greater relative contribution to OSA pathogenesis in these patients. Contrastingly, the prevalence of a highly collapsible upper airway in COMISA was low, suggesting that anatomical predisposition may contribute less to OSA development in COMISA. Based on our findings, we theorize that conditioned hyperarousal perpetuating insomnia may translate to a reduced arousal threshold to respiratory events, thereby increasing the risk or severity of OSA. Therapies that target increased nocturnal hyperarousal (e.g., through cognitive behavior therapy for insomnia) may be effective in individuals with COMISA. Clinical trial registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12616000586415).

Oronasal vs Nasal Masks: The Impact of Mask Type on CPAP Requirement, Pharyngeal Critical Closing Pressure (Pcrit), and Upper Airway Cross-Sectional Areas in Patients With OSA.

BACKGROUND: CPAP delivered via an oronasal mask is associated with lower adherence, higher residual apnea-hypopnea index (AHI), and increased CPAP therapeutic pressure compared with nasal masks. However, the mechanisms underlying the increased pressure requirements are not well understood. RESEARCH QUESTION: How do oronasal masks affect upper airway anatomy and collapsibility? STUDY DESIGN AND METHODS: Fourteen patients with OSA underwent a sleep study with both a nasal and oronasal mask, each for one-half of the night (order randomized). CPAP was manually titrated to determine therapeutic pressure. Upper airway collapsibility was assessed using the pharyngeal critical closing pressure (Pcrit) technique. Cine MRI was done to dynamically assess the cross-sectional area of the retroglossal and retropalatal airway throughout the respiratory cycle with each mask interface. Scans were repeated at 4 cm H2O and at the nasal and oronasal therapeutic pressures. RESULTS: The oronasal mask was associated with higher therapeutic pressure requirements (ΔM ± SEM; +2.6 ± 0.5; P < .001) and higher Pcrit (+2.4 ± 0.5 cm H2O; P = .001) compared with the nasal mask. The change in therapeutic pressure between masks was strongly correlated with the change in Pcrit (r2 = 0.73; P = .003). Increasing CPAP increased both the retroglossal and retropalatal airway dimensions across both masks. After controlling for pressure and breath phase, the retropalatal cross-sectional area was moderately larger when using a nasal vs an oronasal mask (+17.2 mm2; 95% CI, 6.2-28.2, P < .001) while nasal breathing. INTERPRETATION: Oronasal masks are associated with a more collapsible airway than nasal masks, which likely contributes to the need for a higher therapeutic pressure.

A single dose of noradrenergic/serotonergic reuptake inhibitors combined with an antimuscarinic does not improve obstructive sleep apnoea severity.

Previous trials have demonstrated that the combination of noradrenergic reuptake inhibitors with an antimuscarinic can substantially reduce the apnoea-hypopnoea index (AHI) and improve airway collapsibility in patients with obstructive sleep apnoea (OSA). However, some studies have shown that when administered individually, neither noradrenergic or serotonergic agents have been effective at alleviating OSA. This raises the possibility that serotonergic agents (like noradrenergic agents) may also need to be delivered in combination to be efficacious. Therefore, we investigated the effect of an antimuscarinic (oxybutynin) on OSA severity when administered with either duloxetine or milnacipran, two dual noradrenergic/serotonergic reuptake inhibiters. A randomized, double-blind, 4 way cross-over, placebo-controlled trial in ten OSA patients was performed. Patients received each drug condition separately across four overnight in-lab polysomnography (PSG) studies ~1-week apart. The primary outcome measure was the AHI. In addition, the four key OSA endotypes (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non-invasively from the PSGs using validated techniques. There was no significant effect of either drug combinations on reducing the total AHI or improving any of the key OSA endotypes. However, duloxetine+oxybutynin did significantly increase the fraction of hypopnoeas to apnoeas (FHypopnoea ) compared to placebo (p = 0.02; d = 0.54). In addition, duloxetine+oxybutynin reduced time in REM sleep (p = 0.009; d = 1.03) which was positively associated with a reduction in the total AHI (R2  = 0.62; p = 0.02). Neither drug combination significantly improved OSA severity or modified the key OSA endotypes when administered as a single dose to unselected OSA patients.

Examining the impact of multilevel upper airway surgery on the obstructive sleep apnoea endotypes and their utility in predicting surgical outcomes.

BACKGROUND AND OBJECTIVE: Upper airway surgery for obstructive sleep apnoea (OSA) is an alternative treatment for patients who are intolerant of continuous positive airway pressure (CPAP). However, upper airway surgery has variable treatment efficacy with no reliable predictors of response. While we now know that there are several endotypes contributing to OSA (i.e., upper airway collapsibility, airway muscle response/compensation, respiratory arousal threshold and loop gain), no study to date has examined: (i) how upper airway surgery affects all four OSA endotypes, (ii) whether knowledge of baseline OSA endotypes predicts response to surgery and (iii) whether there are any differences when OSA endotypes are measured using the CPAP dial-down or clinical polysomnographic (PSG) methods. METHODS: We prospectively studied 23 OSA patients before and ≥3 months after multilevel upper airway surgery. Participants underwent clinical and research PSG to measure OSA severity (apnoea-hypopnoea index [AHI]) and endotypes (measured in supine non-rapid eye movement [NREM]). Values are presented as mean ± SD or median (interquartile range). RESULTS: Surgery reduced the AHITotal (38.7 [23.4 to 79.2] vs. 22.0 [13.3 to 53.5] events/h; p = 0.009). There were no significant changes in OSA endotypes, however, large but variable improvements in collapsibility were observed (CPAP dial-down method: ∆1.9 ± 4.9 L/min, p = 0.09, n = 21; PSG method: ∆3.4 [-2.8 to 49.0]%Veupnoea , p = 0.06, n = 20). Improvement in collapsibility strongly correlated with improvement in AHI (%∆AHISupineNREM vs. ∆collapsibility: p < 0.005; R2  = 0.46-0.48). None of the baseline OSA endotypes predicted response to surgery. CONCLUSION: Surgery unpredictably alters upper airway collapsibility but does not alter the non-anatomical endotypes. There are no baseline predictors of response to surgery.

Body position during laboratory and home polysomnography compared to habitual sleeping position at home.

STUDY OBJECTIVES: Supine-predominant obstructive sleep apnea (OSA) is highly prevalent. The proportion of time spent in the supine position may be overrepresented during polysomnography, which would impact on the apnea-hypopnea index (AHI) and have important clinical implications. We aimed to investigate the difference in body position during laboratory or home polysomnography compared to habitual sleep and estimate its effect on OSA severity. Secondary aims were to evaluate the consistency of habitual sleeping position and accuracy of self-reported sleeping position. METHODS: Patients undergoing diagnostic laboratory or home polysomnography were recruited. Body position was recorded using a neck-worn device. Habitual sleeping position was the average time spent supine over 3 consecutive nights at home. Primary outcomes were the proportion of sleep time spent supine (% time supine) and AHI adjusted for habitual sleeping position. RESULTS: Fifty-seven patients who underwent laboratory polysomnography and 56 who had home polysomnography were included. Compared to habitual sleep, % time supine was higher during laboratory polysomnography (mean difference 14.1% [95% confidence interval: 7.2-21.1]; P = .0002) and home polysomnography (7.1% [95% confidence interval 0.9-13.3]; P = .03). Among those with supine-predominant OSA, there was a trend toward lower adjusted AHI than polysomnography-derived AHI (P = .07), changing OSA severity in 31.6%. There was no significant between-night difference in % time supine during habitual sleep (P = .4). Self-reported % time supine was inaccurate (95% limits of agreement -49.2% to 53.9%). CONCLUSIONS: More time was spent in the supine position during polysomnography compared to habitual sleep, which may overestimate OSA severity for almost one-third of patients with supine-predominant OSA. CLINICAL TRIAL REGISTRATION: Registry: Australia and New Zealand Clinical Trials Registry (ANZCTR); Title: Sleeping position during sleep tests and at home; Identifier: ACTRN12618000628246; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374873&isReview=true. CITATION: Yo SW, Joosten SA, Wimaleswaran H, et al. Body position during laboratory and home polysomnography compared to habitual sleeping position at home. J Clin Sleep Med. 2022;18(9):2103-2111.

Assessing the Physiologic Endotypes Responsible for REM- and NREM-Based OSA.

BACKGROUND: Patients with OSA can have the majority of their respiratory events in rapid eye movement (REM) sleep or in non-rapid eye movement (NREM) sleep. No previous studies have linked the different physiologic conditions in REM and NREM sleep to the common polysomnographic patterns seen in everyday clinical practice, namely REM predominant OSA (REMOSA) and NREM predominant OSA (NREMOSA). RESEARCH QUESTION: (1) How does OSA physiologic condition change with sleep stage in patients with NREMOSA and REMOSA? (2) Do patients with NREMOSA and REMOSA have different underlying OSA pathophysiologic conditions? STUDY DESIGN AND METHODS: We recruited patients with three polysomnographic patterns. (1) REMOSA: twice as many respiratory events in REM sleep, (2) NREMOSA: twice as many events in NREM sleep, and (3) uniform OSA: equal number of events in NREM/REM sleep. We deployed a noninvasive phenotyping method to determine OSA endotype traits (Vpassive, Vactive, loop gain, arousal threshold) in NREM sleep, REM sleep, and total night sleep in each group of patients (NREMOSA, REMOSA, uniform OSA). RESULTS: Patients with NREMOSA have significantly worse ventilatory control stability in NREM sleep compared with REM sleep (loop gain, 0.546 [0.456,0.717] in NREM vs 0.365 [0.238,0.459] in REM sleep; P = .0026). Patients with REMOSA displayed a significantly more collapsible airway (ie, lower Vpassive) in REM compared with NREM sleep (98.4 [97.3,99.2] %Veupnea in NREM vs 95.9 [86.4,98.9] %Veupnea in REM sleep; P < .0001). The major between-group difference across the whole night was a significantly higher loop gain in the NREMOSA group (0.561 [0.429,0.675]) compared with the REMOSA group (0.459 [0.388,0.539]; P = .0033). INTERPRETATION: This study is the first to link long-recognized polysomnographic patterns of OSA to underlying physiologic differences. Patients with NREMOSA have a higher loop gain in NREM sleep; patients with REMOSA have a worsening of Vpassive in REM sleep.

A randomized controlled trial of oxygen therapy for patients who do not respond to upper airway surgery for obstructive sleep apnea.

STUDY OBJECTIVES: We aimed to determine whether patients diagnosed with obstructive sleep apnea (OSA) who fail to respond to upper airway surgery may be successfully treated with supplemental oxygen and whether we could identify baseline physiologic endotypes (ie, collapsibility, loop gain, arousal threshold, and muscle compensation) that predict response to oxygen therapy. METHODS: We conducted a single night, randomized double-blinded cross over trial in which patients with OSA who failed to respond to upper airway surgery were treated on separate nights with oxygen therapy (4 L/min) or placebo (medical air). Effect of oxygen/air on OSA on key polysomnography outcomes were assessed: apnea-hypopnea index (AHI), AHI without desaturation (ie, flow-based AHI), arousal index, and morning blood pressure. OSA endotypes were estimated from the polysomnography signals to determine whether baseline OSA physiology could be used to predict response to oxygen therapy. RESULTS: There was a statistically significant reduction in AHI and flow-based AHI on oxygen vs placebo (flow-based AHI: 42.4 ± 21.5 vs 30.5 ± 17.1 events/h, P = .008). Arousal index was also reduced on oxygen vs placebo (41.1 ± 19.5 vs 33.0 ± 15.3 events/h, P = .006). There was no significant difference in morning blood pressure between oxygen and placebo. Although 7 of 20 individuals experienced a 50% reduction or greater in flow-based AHI on oxygen (responders), there was no difference in the baseline OSA endotypes (or clinical characteristics) between responders and nonresponders. CONCLUSIONS: Our findings demonstrate that a proportion of patients who fail to respond to upper airway surgery for OSA respond acutely to treatment with supplemental oxygen. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Oxygen therapy for treating patients with residual obstructive sleep apnea following upper airway surgery; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373566; Identifier: ACTRN12617001361392.

Effect of Hypopnea Scoring Criteria on Noninvasive Assessment of Loop Gain and Surgical Outcome Prediction.

Rationale: Unstable ventilatory control (high loop gain) is a causal factor in the development of obstructive sleep apnea. Methods for quantifying loop gain using polysomnography have been developed that predict favorable responses to upper airway surgery. However, this method is reliant on respiratory event scoring and hence may be affected by hypopnea scoring criteria.Objectives: To determine to what extent differences in hypopnea scoring influence loop gain measurement.Methods: We performed a retrospective analysis of 46 polysomnograms before and after upper airway surgery. Polysomnograms were rescored according to three different American Academy of Sleep Medicine hypopnea definitions (2007Alternative, 2012Recommended, and 2012Acceptable criteria). Loop gain and apnea-hypopnea indexes (AHIs) were compared between criteria using linear regression and Bland-Altman limits of agreement (LOA). Responders to surgery were classified by a 50% or greater reduction in AHI and AHIpostsurgery less than 10 events per hour. Responders were determined separately for each American Academy of Sleep Medicine criterion. Receiver operating characteristic curve analysis predicting surgical outcome was performed for each loop gain measurement derived from each criterion.Results: A near-perfect agreement was found between loop gains derived using the 2007Alternative and 2012Recommended criteria (r2 = 0.99; bias = -0.003; LOA, -0.016 to 0.010). Greater variability was found for 2012Acceptable compared to the 2007Alternative (r2 = 0.70; bias = -0.015; LOA, -0.099 to 0.070) and 2012Recommended (r2 = 0.69; bias = +0.018; LOA, -0.068 to 0.104) criteria. Both 2007Alternative and 2012Recommended loop gains significantly predicted surgical response with similar areas under the curve (AUCs; 2007Alternative AUC = 0.86 [95% confidence interval (CI), 0.75-0.97]; 2012Recommended AUC = 0.84 [95% CI, 0.71-0.97]). 2012Acceptable loop gains were a poor predictor of surgical response (AUC = 0.62 [95% CI, 0.43-0.80]).Conclusions: Loop gain measured noninvasively by polysomnography can be influenced by respiratory event scoring. We recommend caution when using the 2012Acceptable criteria with this method, because such findings may not be directly generalizable to other loop gain values derived from other scoring criteria.

Xen45 Gel Stent implant: patient reported outcomes.

Our aim was to report quality of life (QOL) outcomes following Xen45 Gel Stent implantation surgery in patients suffering with primary open angle glaucoma (POAG). A retrospective analysis was performed on all patients who had Xen45 implantation surgery during a 2-year period (Jun, 2016-Apr, 2018). Of 52 consecutive patients were included with a total of 58 eyes being operated on. QOL was compared both pre-operatively and 6 weeks post-operatively using the GQL-15 questionnaire. There was an overall improvement in GQL-15 summary scores for our patient group. All item scores showed either no change or some degree of improvement. The Xen45 Gel Stent Implant is a promising new intervention which has shown improved QOL scores in our patient group. Further, higher power studies are now needed to compare the Xen45 to trabeculectomy (TE), which is currently the gold standard.