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Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx)., Objective: To investigate the role of mouth breathing as an essential route in some patients with OSA and its association with upper airway anatomical factors., Design, Setting, and Participants: This nonrandomized clinical trial included participants diagnosed with OSA who underwent drug-induced sleep endoscopy. Patients were stratified into 3 quantiles based on oral-breathing level (quantile 1: oral airflow < 0.05 L/min; quantile 2: oral airflow 0.05-2.2 L/min; quantile 3: oral airflow > 2.2 L/min)., Interventions: Closing the mouth during sleep during alternating breaths by applying pressure to the mentum until teeth are in occlusion., Main Outcomes and Measures: The primary outcome was total inspiratory flow defined as the change in airflow in the transition from mouth relaxed to mouth closed, analyzed overall and by 3 oral-breathing quantiles. The association of velopharyngeal obstruction on the change in total inspiratory airflow was also investigated., Results: Of 66 enrolled patients with OSA, 12 were excluded due to insufficient baseline airflow. The analytic cohort consisted of 54 patients (39 [72%] male; median [IQR] age, 55 [46-64] years; apnea-hypopnea index, 26.9 [17.6-39.9] events/h; and body mass index calculated as weight in kilograms divided by height in meters squared, 28.9 [27.1-31.6]). Mouth closure increased total inspiratory flow by 27.8 percentage points overall (β, 1.0 [95% CI, 0.4-1.9] L/min). However, outcomes varied based on the degree of baseline oral breathing. No association was found for 10 patients with near-zero mouth breathing (0.9 [95% CI, -0.2 to 2.1] L/min). Airflow improved with mouth closure in 32 patients with moderate levels of mouth breathing (2.0 [95% CI, 1.3-2.7] L/min), whereas it worsened in patients with high levels of mouth breathing (-1.9 [95% CI, -3.1 to -0.6] L/min). Velopharyngeal obstruction was associated with increased mouth breathing (0.6 [95% CI, 0.1-3.0] L/min) and reduced airflow with mouth closure (-1.9 [95% CI, -3.1 to -0.7] L/min)., Conclusion and Relevance: Although mouth closure increased inspiratory airflow in the overall cohort of this nonrandomized clinical trial, the outcomes were heterogeneous. In patients who breathe primarily through their mouth during sleep and have velopharyngeal obstruction, airflow worsens with mouth closure. Hence, personalized approaches to treating mouth breathing should be considered., Trial Registration: ClinicalTrials.gov Identifier: NCT06547658.

Background: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b)., Methods: Flow limitation severity scores (0%=fully obstructed, 100%=open airway), quantified from breath-by-breath airflow shape, were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and pre-eclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and infant birthweight., Results: Of 1939 participants with flow limitation data at both time-points (mean±sd age 27.0±5.4 years and BMI 27.7±6.1 kg·m -2 ), 5.8% developed pre-eclampsia, 12.7% developed HDP and 4.5% developed GDM. Greater flow limitation was associated with increased pre-eclampsia risk: adjusted OR 2.49 (95% CI 1.69-3.69) per 2sd increase in severity. Findings persisted in women without sleep apnoea (apnoea-hypopnoea index <5 events·h -1 ). Flow limitation was associated with HDP (OR 1.77 (95% CI 1.33-2.38)) and reduced infant birthweight (83.7 (95% CI 31.8-135.6) g), but not GDM., Conclusions: Greater flow limitation is associated with increased risk of pre-eclampsia, HDP and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy., Competing Interests: Conflict of interest: A. Azarbarzin receives personal fees as a consultant for Somnifix, Apnimed, LinguaFlex, Respicardia and Inspire, and receives grant support from Somnifix. A. Wellman has financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnoea; his interests are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict of interest policies; A. Wellman also consults for Apnimed, Nox Medical, Inspire, Somnifix, Mosanna and Takeda, and has received grants from Somnifix and Sanofi. P.C. Zee receives personal fees as a consultant from Eisai, Jazz, Idorsia, Harmony Bioscience, Sleep Number and CVS Caremark. S. Redline received personal fees from Jazz Pharma, Eli Lilly and Apnimed. S.A. Sands receives personal fees as a consultant for Nox Medical, Merck, Apnimed, Respicardia, Inspire, Lilly, LinguaFlex and Forepont outside the submitted work, and receives grant support from Apnimed, ProSomnus and Dynaflex for unrelated studies. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Differences in the pharyngeal site of collapse influence efficacy of non-continuous positive airway pressure therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the level of the palate (CCCp) during drug-induced sleep endoscopy (DISE) is associated with reduced efficacy of hypoglossal nerve stimulation, but CCCp is currently not recognisable using polysomnography. Here we develop a means to estimate DISE-based site of collapse using overnight polysomnography., Methods: 182 OSA patients provided DISE and polysomnography data. Six polysomnographic flow shape characteristics (mean during hypopnoeas) were identified as candidate predictors of CCCp (primary outcome variable, n=44/182), including inspiratory skewness and inspiratory scoopiness. Multivariable logistic regression combined the six characteristics to predict clear presence (n=22) versus absence (n=128) of CCCp (partial collapse and concurrent tongue base collapse excluded). Odds ratios for actual CCCp between predicted subgroups were quantified after cross-validation. Secondary analyses examined complete lateral wall, tongue base or epiglottis collapse. External validation was performed on a separate dataset (n total =466)., Results: CCCp was characterised by greater scoopiness (β=1.5±0.6 per 2sd, multivariable estimate±se) and skewness (β=11.4±2.4) compared with non-CCCp. The odds ratio for CCCp in predicted positive versus negative subgroups was 5.0 (95% CI 1.9-13.1). The same characteristics provided significant cross-validated prediction of lateral wall (OR 6.3, 95% CI 2.4-16.5), tongue base (OR 3.2, 95% CI 1.4-7.3) and epiglottis (OR 4.4, 95% CI 1.5-12.4) collapse. CCCp and lateral wall collapse shared similar characteristics (skewed, scoopy), diametrically opposed to tongue base and epiglottis collapse characteristics. External validation confirmed model prediction., Conclusions: The current study provides a means to recognise patients with likely CCCp or other DISE-based site of collapse categories using routine polysomnography. Since site of collapse influences therapeutic responses, polysomnographic airflow shape analysis could facilitate precision site-specific OSA interventions., Competing Interests: Conflict of interest: S. Op de Beeck reports grants and travel support from Research Foundation Flanders (FWO). D. Vena receives personal fees as a consultant for Inspire Medical Systems. A. Azarbarzin receives personal fees as a consultant for Somnifix, ZOLL Respicardia, Eli Lilly and Apnimed, and receives grant support from Somnifix, American Heart Association and American Academy of Sleep Medicine; in addition, A. Azarbarzin reports receipt of equipment from Philips Respironics, and the following patents: System and method for endo-phenotyping and risk stratifying obstructive sleep apnea, and Method, non-transitory computer readable medium and apparatus for arousal intensity scoring. P. Huyett is an education consultant for Inspire Medical Systems, and reports grants from Inspire Medical Systems and Nyxoah. J. Verbraecken reports grants and fees from SomnoMed, AstraZeneca, AirLiquide, Atos Medical, Vivisol, Mediq Tefa, Medidis, Micromed OSG, Bioprojet, Desitin, Epilog, Idorsia, Nightbalance, Inspire Medical Systems, Heinen and Löwenstein, Ectosense, Philips, ProSomnus, ResMed, Sefam, SD Worx, SOS Oxygène, Tilman, Total Care, Vlaamse Gemeenschap, Vlerick and ZOLL Itamar, and consultancy for Bioprojet, Idorsia and Epilog. A. Wellman works as a consultant for Apnimed, Somnifix, Inspire, Mosana, Takeda and Nox, and has received grants from the National Institutes of Health, Somnifix and Sanofi; in addition, A. Wellman has a financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnoea, and holds a patent on flow shape analysis to detect the site of airway collapse. O.M. Vanderveken reports research support at Antwerp University Hospital outside the submitted work from ProSomnus, SomnoMed, Philips, Inspire Medical Systems, Nyxoah, Med-El and Cochlear, lecture honoraria from SomnoMed and Inspire Medical Systems, and consultancy for SomnoMed, Inspire Medical Systems and GlaxoSmithKline. S.A. Sands has served as a consultant for Apnimed, Nox Medical, Eli Lilly, Merck, LinguaFlex, Respicardia, Forepont and Inspire Medical, received grant support from Apnimed, ProSomnus, and Dynaflex, received royalties from the licensing of IP for pharmacological therapy for OSA, unrelated to the current study, lecture honoraria from Tufts University, and equipment from Nox Medical; his industry interactions are actively managed by his institution and has the following patents: Co-inventor on a patent for a combination pharmacological therapy therapy and Co-inventor on a patent OSA phenotyping using wearable technology. The remaining authors have not potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Breathing effort is important to quantify to understand mechanisms underlying central and obstructive sleep apnea, respiratory-related arousals, and the timing and effectiveness of invasive or noninvasive mechanically assisted ventilation. Current quantitative methods to evaluate breathing effort rely on inspiratory esophageal or epiglottic pressure swings or changes in diaphragm electromyographic (EMG) activity, where units are problematic to interpret and compare between individuals and to measured ventilation. This paper derives a novel method to quantify breathing effort in units directly comparable with measured ventilation by applying respiratory mechanics first principles to convert continuous transpulmonary pressure measurements into "attempted" airflow expected to have arisen without upper airway obstruction. The method was evaluated using data from 11 subjects undergoing overnight polysomnography, including six patients with obesity with severe obstructive sleep apnea (OSA), including one who also had frequent central events, and five healthy-weight controls. Classic respiratory mechanics showed excellent fits of airflow and volume to transpulmonary pressures during wake periods of stable unobstructed breathing (means ± SD, r 2 = 0.94 ± 0.03), with significantly higher respiratory system resistance in patients compared with healthy controls (11.2 ± 3.3 vs. 7.1 ± 1.9 cmH 2 O·L -1 ·s, P = 0.032). Subsequent estimates of attempted airflow from transpulmonary pressure changes clearly highlighted periods of acute and prolonged upper airway obstruction, including within the first few breaths following sleep onset in patients with OSA. This novel technique provides unique quantitative insights into the complex and dynamically changing interrelationships between breathing effort and achieved airflow during periods of obstructed breathing in sleep. NEW & NOTEWORTHY Ineffective breathing efforts with snoring and obstructive sleep apnea (OSA) are challenging to quantify. Measurements of esophageal or epiglottic pressure swings and diaphragm electromyography are useful, but units are problematic to interpret and compare between individuals and to measured ventilation. This paper derives a novel method that uses esophageal pressure and respiratory mechanics first principles to quantify breathing effort as "attempted" flow and volume in units directly comparable with measured airflow, volume, and ventilation.

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., Competing Interests: Competing interests: The combination intervention under investigation in the current study was protected by a patent ('Combination pharmacological interventions for multiple mechanisms of obstructive sleep apnoea', WO-2021091902-A1, Sands co-inventor) licensed to Apnimed from the Brigham and Women’s Hospital. SS has received grant funding from Apnimed, Prosomnus and Dynaflex, and has served as a consultant for Apnimed, Nox Medical, Inspire, Eli Lilly, Merck, Forepont, LinguaFlex, Achaemenid. He is also co-inventor on a patent related to wearable oximetry technology. He has received royalties from licensed intellectual property. AA served as a consultant for Somnifix, Respicardia and Apnimed; SS and AA’s industry interactions are managed by the Brigham and Women’s Hospital. SJ and GH has received equipment to support research projects from Resmed, Philips Respironics and Air Liquide Healthcare. BE has received grant funding from Apnimed and Incannex, and received personal fees from Signifier Medical outside the current work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R  = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, β drive :β pressure ; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half ( n  = 22 of 42) exhibited drive-dominant responses (i.e., β drive :β pressure  > 2:1), and one-quarter ( n  = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., β drive :β pressure  < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] % baseline /standard deviation of β drive :β pressure ; P  = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N  = 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (+19 events/h per 11 kg/m 2 [2 SD]), male sex (+13 events/h vs. female), older age (+7 events/h per 20 yr), and Chinese ancestry (+5 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (+0.40 SD) and greater loop gain (+0.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (+0.86 SD) and reduced compensation (-0.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (+0.37 SD) and greater loop gain (+0.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (+0.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (-0.30 SD) and elevated loop gain (+0.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.

Background and Objective: The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes., Methods: Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per V MIN and arousal threshold) were derived from validated algorithms., Results: Compared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p = 0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p = 0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p = 0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p = 0.093). Ato-Feso lowered collapsibility (raised V MIN ; 43.7 [29.8-55.7] vs. 56.8 [43.8-69.8] %V EUPNOEA , mean [CI], p = 0.002), but reduced the arousal threshold (129.3 [120.1-138.6] vs. 116.7 [107.5-126] %V EUPNOEA , p = 0.038). In post hoc analysis, 6/6 patients with milder collapsibility (V MIN  > 43%) exhibited OSA resolution (drop in AHI > 50% and residual AHI < 10 events/h) and improved hypoxaemia., Conclusion: While inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals., (© 2022 Asian Pacific Society of Respirology.)

Study Objectives: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h)., Methods: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs. N windows available) provided a recommended amount of data for acceptable repeatability (Rthreshold = 0.7). Long-term consistency was assessed using the Osteoporotic Fractures in Men Study (MrOS) at two time points 6.5 ± 0.7 years apart, before and after accounting for across-year body position and sleep state differences. Within-night dependence of traits on position and state (MESA plus MrOS data) was estimated using bootstrapping., Results: Within-night repeatability for traits ranged from R = 0.62-0.79 and improved to R = 0.69-0.83 when recommended amounts of data were available (20-35 7-min windows, available in 94%-98% of participants); repeatability was similar for collapsibility, loop gain, and arousal threshold (R = 0.79-0.83), but lower for compensation (R = 0.69). Long-term consistency was modest (R = 0.30-0.61) and improved (R = 0.36-0.63) after accounting for position and state differences. Position/state analysis revealed reduced loop gain in REM and reduced collapsibility in N3., Conclusions: Endotypic traits can be obtained with acceptable repeatability. Long-term consistency was modest but improved after accounting for position and state changes. These data support the use of endotypic assessments in large-scale epidemiological studies., Clinical Trial Information: The data used in the manuscript are from observational cohort studies and are not a part of the clinical trial., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory 'drive'. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements., Methods: In 50 OSA patients (5-91 events/hour), we recorded ventilation ('flow', oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight. Flow and drive during events were ensemble averaged; patients were classified as drive dependent if flow fell/rose simultaneously with drive. Overnight effects of lower drive on flow, genioglossus muscle activity (EMGgg) and event risk were quantified (mixed models)., Results: On average, ventilatory drive fell (rather than rose) during events (-20 (-42 to 3)% baseline , median (IQR)) and was strongly correlated with flow (R=0.78 (0.24 to 0.94)). Most patients (30/50, 60%) were classified as exhibiting drive-dependent event pathophysiology. Lower drive during sleep was associated with lower flow (-17 (-20 to -14)%/drive) and EMGgg (-3.5 (-3.8 to -3.3)% max /drive) and greater event risk (OR: 2.2 (1.8 to 2.5) per drive reduction of 100% eupnoea ); associations were concentrated in patients with drive-dependent OSA (ie, flow: -37 (-40 to -34)%/drive, OR: 6.8 (5.3 to 8.7)). Oesophageal pressure-without tidal volume correction-falsely suggested rising drive during events ( classic model)., Conclusions: In contrast to the prevailing view, patients with OSA predominantly exhibit drive-dependent event pathophysiology, whereby flow is lowest at nadir drive, and lower drive raises event risk. Preventing ventilatory drive decline is therefore considered a target for OSA intervention., Competing Interests: Competing interests: SS received grant support from Apnimed, Prosomnus and Dynaflex and has served as a consultant for Apnimed, Nox Medical and Merck. DPW is a distinguished scientist with Apnimed and a consultant for RBNC Therateutics, Philips Respironics, Cryosa and Cerebra Health. AA serves as consultant for Somnifix and Apnimed and receives grant support from Somnifix. AW works as a consultant for Apnimed, Nox, Inspire and Somnifix and has received grants from Sanofi and Somnifix. LT-M works as medical director at Apnimed. AW and LT-M have a financial interest in Apnimed Inc, a company developing pharmacological therapies for sleep apnoea; their interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Esophageal and epiglottic pressure deflections are widely used to quantify ventilatory effort during sleep in patients with obstructive sleep apnea (OSA). However, changes in upper airway patency will fundamentally alter pressure gradients across the respiratory system with different airflow and volume-dependent effects on esophageal versus epiglottic pressure. The magnitude of these obstruction effects on ventilatory effort assessed from pressure deflections has not been systematically investigated. This study sought to quantify the direct effect of airway occlusion on esophageal and epiglottic pressure deflections during sleep in patients with OSA compared with predictions based on classic respiratory mechanics. Pneumotachograph airflow and volume, and esophageal, epiglottic, mask, and gastric pressures were measured throughout a nonoccluded breath before and the first occluded breath after repeated external airway occlusions during sleep in 13 patients with OSA on constant positive airway pressure (CPAP). Inspiratory pressure deflections were approximately doubled with epiglottic pressure, and increased by around 40% with esophageal pressure on the occluded compared with the preoccluded breath. Differences in pressure between pre- and occluded breaths showed strong dependence on volume and flow, in line with theoretical models of respiratory mechanics. A relatively simple correction factor could account for these effects to provide more consistent measures of ventilatory effort from pressure, independent from measurement site and changing airflow conditions. These finding have important implications for interpreting ventilatory effort and arousal threshold measurements and for understanding the relationships between underlying ventilatory drive and pressure deflections in the presence of airway obstruction during sleep. NEW & NOTEWORTHY Esophageal and epiglottic pressure deflection measurements are widely used as gold-standard measures of ventilatory effort without consideration of differential obstruction effects between measurement sites. This study is the first to quantify the effect of airway occlusion on pressure recordings during sleep. The findings of substantial acute effects of occlusion itself on pressure deflections are important to consider in the planning, analysis, and interpretation of studies that make inferences regarding inspiratory effort.