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RATIONALE: Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1). OBJECTIVES: To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2[pi]/(2[pi]DR - sin2[pi]DR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB. METHODS: After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB. MEASUREMENTS AND MAIN RESULTS: In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 ± 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 ± 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 ± 0.04 versus 1.10 ± 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients. CONCLUSIONS: Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy. [ABSTRACT FROM AUTHOR]

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/m 2 ). 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).

Rationale: Preterm infants are at risk for ventilatory control instability that may be due to aberrant peripheral chemoreceptor activity. Although term infants have increasing peripheral chemoreceptor contribution to overall ventilatory drive with increasing postnatal age, how peripheral chemoreceptor contribution changes in preterm infants with increasing postmenstrual age is not known. Objectives: To evaluate peripheral chemoreceptor activity between 32 and 52 weeks postmenstrual age in preterm infants, using both quantitative and qualitative measures. Methods: Fifty-five infants born between 24 weeks, 0 days gestation and 28 weeks, 6 days gestation underwent hyperoxic testing at one to four time points between 32 and 52 weeks postmenstrual age. Quantitative [Formula: see text] decreases were calculated, and qualitative responses were categorized as apnea, continued breathing with a clear reduction in [Formula: see text], sigh breaths, and no response. Measurements and Main Results: A total of 280 hyperoxic tests were analyzed (2.2 ± 0.3 tests per infant at each time point). Mean peripheral chemoreceptor contribution to ventilatory drive was 85.2 ± 20.0% at 32 weeks and 64.1 ± 22.0% at 52 weeks. Apneic responses were more frequent at earlier postmenstrual ages. Conclusions: Among preterm infants, the peripheral chemoreceptor contribution to ventilatory drive was greater at earlier postmenstrual ages. Apnea was a frequent response to hyperoxic testing at earlier postmenstrual ages, suggesting high peripheral chemoreceptor activity. A clearer description of how peripheral chemoreceptor activity changes over time in preterm infants may help explain how ventilatory control instability contributes to apnea and sleep-disordered breathing later in childhood. Clinical trial registered with www.clinicaltrials.gov (NCT03464396).

Continuous positive airway pressure (CPAP) remains the major treatment option for obstructive sleep apnea (OSA). The American Thoracic Society organized a workshop to discuss the importance of mask selection for OSA treatment with CPAP. In this workshop report, we summarize available evidence about the breathing route during nasal and oronasal CPAP and the importance of nasal symptoms for CPAP outcomes. We explore the mechanisms of air leaks during CPAP treatment and possible alternatives for leak control. The impact of nasal and oronasal CPAP on adherence, residual apnea-hypopnea index, unintentional leaks, and pressure requirements are also compared. Finally, recommendations for patient and partner involvement in mask selection are presented, and future directions to promote personalized mask selection are discussed.

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 (2007 Alternative , 2012 Recommended , and 2012 Acceptable 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 AHI postsurgery 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 2007 Alternative and 2012 Recommended criteria ( r 2  = 0.99; bias = -0.003; LOA, -0.016 to 0.010). Greater variability was found for 2012 Acceptable compared to the 2007 Alternative ( r 2  = 0.70; bias = -0.015; LOA, -0.099 to 0.070) and 2012 Recommended ( r 2  = 0.69; bias = +0.018; LOA, -0.068 to 0.104) criteria. Both 2007 Alternative and 2012 Recommended loop gains significantly predicted surgical response with similar areas under the curve (AUCs; 2007 Alternative AUC = 0.86 [95% confidence interval (CI), 0.75-0.97]; 2012 Recommended AUC = 0.84 [95% CI, 0.71-0.97]). 2012 Acceptable 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 2012 Acceptable criteria with this method, because such findings may not be directly generalizable to other loop gain values derived from other scoring criteria.

Rationale: Oral appliance therapy is efficacious in many patients with obstructive sleep apnea (OSA), but prediction of treatment outcome is challenging. Small, detailed physiological studies have identified key OSA endotypic traits (pharyngeal collapsibility and loop gain) as determinants of greater oral appliance efficacy. Objectives: We used a clinically applicable method to estimate OSA traits from routine polysomnography and identify an endotype-based subgroup of patients expected to show superior efficacy. Methods: In 93 patients (baseline apnea-hypopnea index [AHI], ≥20 events/h), we examined whether polysomnography-estimated OSA traits (pharyngeal: collapsibility and muscle compensation; nonpharyngeal: loop gain, arousal threshold, and ventilatory response to arousal) were associated with oral appliance efficacy (percentage reduction in AHI from baseline) and could predict responses to treatment. Multivariable regression (with interactions) defined endotype-based subgroups of "predicted" responders and nonresponders (based on 50% reduction in AHI). Treatment efficacy was compared between the predicted subgroups (with cross-validation). Results: Greater oral appliance efficacy was associated with favorable nonpharyngeal traits (lower loop gain, higher arousal threshold, and lower response to arousal), moderate (nonmild, nonsevere) pharyngeal collapsibility, and weaker muscle compensation (overall R 2  = 0.30; adjusted R 2  = 0.19; P  = 0.003). Predicted responders ( n  = 54), compared with predicted nonresponders ( n  = 39), exhibited a greater reduction in AHI from baseline (mean [95% confidence interval], 73% [66-79] vs. 51% [38-61]; P  < 0.0001) and a lower treatment AHI (8 [6-11] vs. 16 [12-20] events/h; P  = 0.002). Differences persisted after adjusting for clinical covariates (including baseline AHI, body mass index, and neck circumference). Conclusions: Quantifying OSA traits using clinical polysomnography can identify an endotype-based subgroup of patients that is highly responsive to oral appliance therapy. Prospective validation is warranted.

Traditionally, the presence and severity of obstructive sleep apnea (OSA) have been defined by the apnea-hypopnea index (AHI). Continuous positive airway pressure is generally first-line therapy despite low adherence, because it reliably reduces the AHI when used, and the response to other therapies is variable. However, there is growing appreciation that the underlying etiology (i.e., endotype) and clinical manifestation (i.e., phenotype) of OSA in an individual are not well described by the AHI. We define and review the important progress made in understanding and measuring physiological mechanisms (or endotypes) that help define subtypes of OSA and identify the potential use of genetics to further refine disease classification. This more detailed understanding of OSA pathogenesis should influence clinical treatment decisions as well as help inform research priorities and clinical study design. In short, treatments could be individualized on the basis of the underlying cause of OSA; patients could better understand which symptoms and outcomes will respond to OSA treatment and by how much; and researchers could select populations most likely to benefit from specific treatment approaches for OSA.

Rationale: There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. Objectives: We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea-hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA. Methods: A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato-oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately. Measurements and Main Results: The participants' median (interquartile range) age was 53 (46-58) years and body mass index was 34.8 (30.0-40.2) kg/m 2 . ato-oxy lowered AHI by 63% (34-86%), from 28.5 (10.9-51.6) events/h to 7.5 (2.4-18.6) events/h ( P  < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62-88%) ( P  < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1-4.7)%/cm H 2 O on placebo to 6.3 (3.0 to 18.3)%/cm H 2 O on ato-oxy ( P  < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately. Conclusions: A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA. Clinical trial registered with www.clinicaltrials.gov (NCT02908529).

Rationale: Therapies for obstructive sleep apnea (OSA) could be administered on the basis of a patient's own phenotypic causes ("traits") if a clinically applicable approach were available., Objectives: Here we aimed to provide a means to quantify two key contributors to OSA-pharyngeal collapsibility and compensatory muscle responsiveness-that is applicable to diagnostic polysomnography., Methods: Based on physiological definitions, pharyngeal collapsibility determines the ventilation at normal (eupneic) ventilatory drive during sleep, and pharyngeal compensation determines the rise in ventilation accompanying a rising ventilatory drive. Thus, measuring ventilation and ventilatory drive (e.g., during spontaneous cyclic events) should reveal a patient's phenotypic traits without specialized intervention. We demonstrate this concept in patients with OSA (N = 29), using a novel automated noninvasive method to estimate ventilatory drive (polysomnographic method) and using "gold standard" ventilatory drive (intraesophageal diaphragm EMG) for comparison. Specialized physiological measurements using continuous positive airway pressure manipulation were employed for further comparison. The validity of nasal pressure as a ventilation surrogate was also tested (N = 11)., Measurements and Main Results: Polysomnography-derived collapsibility and compensation estimates correlated favorably with those quantified using gold standard ventilatory drive (R = 0.83, P < 0.0001; and R = 0.76, P < 0.0001; respectively) and using continuous positive airway pressure manipulation (R = 0.67, P < 0.0001; and R = 0.64, P < 0.001; respectively). Polysomnographic estimates effectively stratified patients into high versus low subgroups (accuracy, 69-86% vs. ventilatory drive measures; P < 0.05). Traits were near-identical using nasal pressure versus pneumotach (N = 11, R ≥ 0.98, both traits; P < 0.001)., Conclusions: Phenotypes of pharyngeal dysfunction in OSA are evident from spontaneous changes in ventilation and ventilatory drive during sleep, enabling noninvasive phenotyping in the clinic. Our approach may facilitate precision therapeutic interventions for OSA.

Rationale: The reduction in upper airway muscle activity from wakefulness to sleep plays a key role in the development of obstructive sleep apnea. Potassium (K + ) channels have been recently identified as the downstream mechanisms through which hypoglossal motoneuron membrane excitability is reduced both in non-rapid eye movement (NREM) sleep and REM sleep. In animal models, the administration of 4-aminopyridine (4-AP), a voltage-gated K + channel blocker, increased genioglossus activity during wakefulness and across all sleep stages., Objectives: We tested the hypothesis that administration of a single dose of 4-AP 10 mg extended release would increase genioglossus activity (electromyography of the genioglossus muscle [EMG GG ]) during wakefulness and sleep, and thereby decrease pharyngeal collapsibility., Methods: We performed a randomized controlled crossover proof-of-concept trial in 10 healthy participants. Participants received active treatment or placebo in randomized order 3 hours before bedtime in the physiology laboratory., Results: EMG GG during wakefulness and NREM sleep and upper airway collapsibility measured during NREM sleep were unchanged between placebo and 4-AP nights. Tonic but not phasic EMG GG during REM sleep was higher on the 4-AP night when measured as a percentage of maximal voluntary activation (median [interquartile range] 0.3 [0.5] on placebo vs. 0.8 [1.9] % max on 4 AP; P = 0.04), but not when measured in μV or as a percentage of wakefulness value., Conclusions: A single dose of 4-AP 10 mg extended release showed only a small increase in tonic EMG GG during REM sleep in this group of healthy subjects. We speculate that a higher dose of 4-AP may further increase EMG GG . However, given the potentially severe, dose-related adverse effects of this drug, including seizures, the administration of 4-AP does not appear to be an effective strategy to increase genioglossus activity during sleep in humans. Clinical Trial registered with clinicaltrials.gov (NCT02656160).

Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO 2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited., Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance "strength") rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects., Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO 2 stimulation., Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain-consequent to increased chemosensitivity and delay-the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = -0.68) oscillations (P < 0.001 for all, both groups combined)., Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population.

Rationale: Oral appliances (OAs) are commonly used as an alternative treatment to continuous positive airway pressure for patients with obstructive sleep apnea (OSA). However, OAs have variable success at reducing the apnea-hypopnea index (AHI), and predicting responders is challenging. Understanding this variability may lie with the recognition that OSA is a multifactorial disorder and that OAs may affect more than just upper-airway anatomy/collapsibility., Objectives: The objectives of this study were to determine how OA alters AHI and four phenotypic traits (upper-airway anatomy/collapsibility and muscle function, loop gain, and arousal threshold), and baseline predictors of which patients gain the greatest benefit from therapy., Methods: In a randomized crossover study, 14 patients with OSA attended two sleep studies with and without their OA. Under each condition, AHI and the phenotypic traits were assessed. Multiple linear regression was used to determine independent predictors of the reduction in AHI., Measurements and Main Results: OA therapy reduced the AHI (30 ± 5 vs. 11 ± 2 events/h; P < 0.05), which was driven by improvements in upper-airway anatomy/collapsibility under passive (1.9 ± 0.7 vs. 4.7 ± 0.6 L/min; P < 0.005) and active conditions (2.4 ± 0.9 vs. 6.2 ± 0.4 L/min; P < 0.001). No changes were seen in muscle function, loop gain, or the arousal threshold. Using multivariate analysis, baseline passive upper-airway collapsibility and loop gain were independent predictors of the reduction in AHI (r 2  = 0.70; P = 0.001)., Conclusions: Our findings suggest that OA therapy improves the upper-airway collapsibility under passive and active conditions. Importantly, a greater response to therapy occurred in those patients with a mild anatomic compromise and a lower loop gain.

Rationale: Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during sleep. To date, there have not been effective methods to reverse pharyngeal hypotonia pharmacologically in sleeping humans., Objectives: We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility., Methods: We conducted a placebo-controlled, double-blind, crossover trial with 10 healthy participants. Participants received active treatment or placebo in randomized order 2 hours before sleep in the physiology laboratory., Measurements and Main Results: Genioglossus activity during wakefulness and sleep, genioglossus muscle responsiveness to negative epiglottic pressure, and upper airway collapsibility during passive and active conditions were compared between on- and off-drug states. Desipramine abolished the normal reduction of genioglossus activity from wakefulness to non-REM sleep that occurred on the placebo night. Specifically, tonic (median, 96% [86-120] vs. 75% [50-92] wakefulness; P = 0.01) but not phasic genioglossus activity was higher with desipramine compared with placebo. Upper airway collapsibility was also reduced with desipramine compared with placebo (-10.0 cm H 2 O [-15.2 to -5.8] vs. -8.1 cm H 2 O [-10.4 to -6.3]; P = 0.037)., Conclusions: Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT02428478).

Rationale: A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea (OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA., Objectives: We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected patients with OSA., Methods: Subjects were studied on two separate nights in a randomized crossover design. Fifteen unselected subjects with OSA (AHI ≥ 10/h) underwent a standard polysomnogram plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100 mg) and placebo, with 1 week between conditions. The arousal threshold was calculated as the nadir pressure before electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly., Measurements and Main Results: Compared with placebo, trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the non-REM arousal threshold (-20.3 vs. -19.3 cm H2O, P = 0.51) compared with placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P = 0.052) and had an accompanying reduction in arousal index, whereas nonresponders were not observed to have a change in sleep parameters., Conclusions: These findings suggest that trazodone could be effective therapy for patients with OSA without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical trial registered with www.clinicaltrials.gov (NCT 01817907).

Rationale: A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements., Objectives: To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH., Methods: Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system., Measurements and Main Results: Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis., Conclusions: Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.

Rationale: Body habitus is a major determinant of obstructive sleep apnea (OSA). However, many individuals do not have OSA despite being overweight/obese (body mass index > 25 kg/m(2)) for reasons that are not fully elucidated., Objectives: To determine the key physiologic traits (upper-airway anatomy/collapsibility, upper-airway muscle responsiveness, chemoreflex control of ventilation, arousability from sleep) responsible for the absence of OSA in overweight/obese individuals., Methods: We compared key physiologic traits in 18 overweight/obese subjects without apnea (apnea-hypopnea index < 15 events per hour) with 25 overweight/obese matched patients with OSA (apnea-hypopnea index ≥ 15 events per hour) and 11 normal-weight nonapneic control subjects. Traits were measured by repeatedly lowering continuous positive airway pressure to subtherapeutic levels for 3 minutes during non-REM sleep., Measurements and Main Results: Overweight/obese subjects without apnea exhibited a less collapsible airway than overweight/obese patients with apnea (critical closing pressure: -3.7 ± 1.9 vs. 0.6 ± 1.2 cm H2O; P = 0.003; mean ± 95% confidence interval), but a more collapsible airway relative to normal-weight control subjects (-8.8 ± 3.1 cm H2O; P < 0.001). Notably, overweight/obese subjects without apnea exhibited a threefold greater upper-airway muscle responsiveness than both overweight/obese patients with apnea (Δgenioglossus EMG/Δepiglottic pressure: -0.49 [-0.22 to -0.79] vs. -0.15 [-0.09 to -0.22] %max/cm H2O; P = 0.008; mean [95% confidence interval]) and normal-weight control subjects (-0.16 [-0.04 to -0.30] %max/cm H2O; P = 0.02). Loop gain was elevated (more negative) in both overweight/obese groups and normal-weight control subjects (P = 0.02). Model-based analysis demonstrated that overweight/obese individuals without apnea rely on both more favorable anatomy and collapsibility and enhanced upper-airway dilator muscle responses to avoid OSA., Conclusions: Overweight/obese individuals without apnea have a moderately compromised upper-airway structure that is mitigated by highly responsive upper-airway dilator muscles to avoid OSA. Elucidating the mechanisms underlying enhanced muscle responses in this population may provide clues for novel OSA interventions.

Rationale: Acetazolamide has been used to attenuate Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) associated with heart failure. However, the mechanisms underlying this improvement remain to be fully elucidated., Objectives: We hypothesized that acetazolamide stabilizes CSA by attenuating the ventilatory sensitivity to CO2, which is increased in patients with heart failure and is thought to be the major mechanism mediating CSA., Methods: Six consecutive male patients with stable systolic heart failure and CSA (apnea-hypopnea index [AHI] ≥ 15 episodes/h) were randomized to a double-blind crossover protocol with acetazolamide or placebo received 1 hour before bedtime for six nights with 2 weeks of wash-out. Under both conditions, we measured the hypercapnic ventilatory response (HCVR), arterial blood Pco2, steady-state metabolic CO2 production, overnight attended polysomnography, and also assessed cardiac and pulmonary function., Measurements and Main Results: Compared with placebo, acetazolamide significantly decreased the AHI (65 ± 32 vs. 31 ± 19 events/h, mean ± SD). Acetazolamide increased the HCVR slope by 55% (3.3 ± 1.7 vs. 5.1 ± 2.4 L/min/mm Hg; P = 0.03), an increase that far exceeded the 12% fall in arterial Pco2 (P = 0.02). The acetazolamide-induced change in the balance of these effects (ΔHCVR × Pco2) was inversely associated with the reduction in AHI (r = 0.8; P = 0.045)., Conclusions: This placebo-controlled study indicates that acetazolamide improves CSA in patients with heart failure despite an increase in the slope of the HCVR. However, because the degree of HCVR elevation inhibits the improvement in unstable breathing, an increased CO2 chemosensitivity may be a key mechanism underlying an incomplete resolution of CSA with acetazolamide.

Rationale: Brief recurrent apneas in preterm infants and adults can precipitate rapid and severe arterial O(2) desaturation for reasons that remain unclear., Objectives: We tested a mathematically derived hypothesis that when breathing terminates apnea, mixed-venous hypoxemia continues into the subsequent apnea; as a result, there is a surge in pulmonary O(2) uptake that rapidly depletes the finite alveolar O(2) store, thereby accelerating arterial O(2) desaturation., Methods: Recurrent apneas were simulated in an experimental lamb model. Pulmonary O(2) uptake was calculated from continuously measured arterial and mixed-venous O(2) saturation and cardiac output., Measurements and Main Results: Direct measurements revealed that asynchrony in the desaturation and resaturation of arterial and venous blood gave rise to dips and surges in O(2) uptake. After desaturation to 50%, a typical nadir in preterm infants, O(2) uptake surged to a peak of 176.9 ± 7.8% of metabolic rate. During subsequent apneas, desaturation rate was increased two- to threefold greater than during isolated apneas, in direct proportion to the magnitude of the surge in O(2) uptake (P < 0.001; R(2) = 0.897). Application of our mathematical model to a published recording of cyclic apneas in a preterm infant precisely reproduced the accelerated desaturation rates of up to 15% · s(-1) observed clinically., Conclusions: Rapid depletion of alveolar O(2) stores by surges in O(2) uptake almost completely explains the acceleration of desaturation that occurs during recurrent apnea. This powerful mechanism is likely to explain the severity of intermittent hypoxemia that is associated with neurocognitive and cardiovascular morbidities in preterm infants and adults.