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.

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).

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.

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.

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.