Elevated Loop Gain Research Articles

Morphological Prediction of CPAP Associated Acute Respiratory Instability.

Multiple mechanisms are involved in the pathogenesis of obstructive sleep apnea (OSA). Elevated loop gain is a key target for precision OSA care and may be associated with treatment intolerance when the upper airway is the sole therapeutic target. Morphological or computational estimation of LG is not yet widely available or fully validated - there is a need for improved phenotyping/endotyping of apnea to advance its therapy and prognosis. This study proposes a new algorithm to assess self-similarity as a signature of elevated loop gain using respiratory effort signals and presents its use to predict the probability of acute failure (high residual event counts) of continuous positive airway pressure (CPAP) therapy. Effort signals from 2145 split-night polysomnography studies from the Massachusetts General Hospital were analyzed for SS and used to predict acute CPAP therapy effectiveness. Logistic regression models were trained and evaluated using 5-fold cross-validation. Receiver operating characteristic (ROC) and precision-recall (PR) curves with AUC values of 0.82 and 0.84, respectively, were obtained. Self-similarity combined with the central apnea index (CAI) and hypoxic burden outperformed CAI alone. Even in those with a low CAI by conventional scoring criteria or only mild desaturation, SS was related to poor therapy outcomes. The proposed algorithm for assessing SS as a measure of expressed high loop gain is accurate, non-invasive, and has the potential to improve phenotyping/endotyping of apnea, leading to more precise sleep apnea treatment strategies.

Mechanisms relating to sleeping position to the endotypes of sleep disordered breathing.

Obstructive sleep apnea (OSA) severity varies considerably depending on the body position during sleep in certain subjects. Such variability may be underpinned by specific, body position-related changes in OSA pathophysiological determinants, or endotypes. Also head position relative to trunk may influence OSA endotypes. However, no studies to our knowledge have reviewed the endotype variations according to head or body position up to now. Several findings illustrate that supine OSA is mostly attributable to unfavorable upper airway anatomy compared to lateral position. However, a reduced lung volume, with consequent ventilatory instability (or elevated loop gain), may also play a role. Furthermore, preliminary findings suggest that prone and reclined positions may have a beneficial effect on collapsibility and loop gain. Sleeping supine induces many unfavorable pathophysiological changes, especially in certain predisposed OSA patients. Little is known on the influence of other sleep positions on key endotypic traits.

Pro: can physiological risk factors for obstructive sleep apnea be determined by analysis of data obtained from routine polysomnography?

This article is a written debate between the author(s) of this article and the author(s) of the opposing argument [1]. The following argument was prepared in response to the question without the knowledge of the contents of the opposing argument. Obstructive sleep apnea (OSA) is a highly prevalent disorder characterized by heterogeneous underlying mechanisms and heterogeneous adverse outcomes. Over the last 20 years, investigators have described how OSA is manifest as a combination of several established physiological risk factors or “endotypic traits”: greater pharyngeal collapsibility, dampened pharyngeal dilator muscle compensation, hyper-responsive ventilatory control (elevated loop gain), and a low arousal threshold (increased arousability from sleep). Evidence for important roles of each pathophysiological pathway are extensive. Profoundly improving pharyngeal collapsibility with CPAP is highly efficacious for resolving OSA, and individuals without a collapsible pharynx (critical collapsing pressure <5 cmH2O) very rarely exhibit OSA [2, 3]; thus, a level of pharyngeal mechanical vulnerability is considered a requirement for OSA. Yet measures of collapsibility alone do not accurately predict the presence/absence of OSA, that is, for the same level of collapsibility some patients exhibit severe OSA and others do not. The two leading endotypic traits responsible for modifying OSA risk are reduced muscle compensation and elevated loop gain. Notably, obese individuals without OSA typically exhibit augmented muscle responses [4], and loop gain is elevated in OSA patients with less-severe collapsibility [5]. A lower arousal threshold is considered to contribute to more severe OSA within participants in lighter non-REM and REM [6].

Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity.

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/m2 [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.

O013 The pathogenesis of obstructive sleep apnea in individuals with comorbid insomnia and obstructive sleep apnoea (COMISA)

Abstract Obstructive sleep apnea (OSA) and Insomnia are prevalent sleep disorders which are highly comorbid. This frequent co-occurrence suggests a shared etiology may exist. OSA is caused by the interaction of four pathophysiological traits: a highly collapsible upper airway, elevated loop gain, a low arousal threshold, and poor muscle compensation. No study has ascertained whether these traits are influenced by insomnia. We aimed to quantify the four traits which contribute to OSA in individuals diagnosed with comorbid insomnia and OSA (COMISA). We non-invasively determined these traits in 52 COMISA patients (Age: 56±14 years) with mild-to-severe OSA (AHI=21.2±10.63 events/h) using polysomnography. Our results indicated that 83% of COMISA patients had a low arousal threshold and only 2% of patients exhibited a highly collapsible airway using previously defined thresholds. Multiple linear regression revealed the arousal threshold (b=0.24, 95%CI[0.11, 0.37], β=0.47, p&amp;lt;0.001) and loop gain (b=23.6, 95%CI[7.02, 40.18], β=0.33, p&amp;lt;0.01) were the strongest predictors of OSA severity in our sample. There was no significant relationship between the arousal threshold and insomnia severity measured by the insomnia severity index (ISI). Further work is being performed to compare these findings with a matched sample of OSA only participants. Our preliminary findings demonstrate OSA in COMISA is characterized by a mildly collapsible airway/low arousal threshold phenotype and is largely driven by non-anatomical factors including a low arousal threshold and high loop gain. OSA treatments which are effective in patients with mild anatomical compromise and raise the arousal threshold may provide therapeutic benefit in COMISA patients.

Mandibular Advancement Device Treatment Efficacy Is Associated with Polysomnographic Endotypes

Rationale: Mandibular advancement device (MAD) treatment efficacy varies among patients with obstructive sleep apnea.Objectives: The current study aims to explain underlying individual differences in efficacy using obstructive sleep apnea endotypic traits calculated from baseline clinical polysomnography: collapsibility (airflow at normal ventilatory drive), loop gain (drive response to reduced airflow), arousal threshold (drive preceding arousal), compensation (increase in airflow as drive increases), and the ventilatory response to arousal (increase in drive explained by arousal). On the basis of previous research, we hypothesized that responders to MAD treatment have a lower loop gain and milder collapsibility.Methods: Thirty-six patients (median apnea-hypopnea index [AHI], 23.5 [interquartile range (IQR), 19.7-29.8] events/h) underwent baseline and 3-month follow-up full polysomnography, with MAD fixed at 75% of maximal protrusion. Traits were estimated using baseline polysomnography according to Sands and colleagues. Response was defined as an AHI reduction ≥ 50%.Results: MAD treatment significantly reduced AHI (49.7%baseline [23.9-63.6], median [IQR]). Responders exhibited lower loop gain (mean [95% confidence interval], 0.53 [0.48-0.58] vs. 0.65 [0.57-0.73]; P = 0.020) at baseline than nonresponders, a difference that persisted after adjustment for baseline AHI and body mass index. Elevated loop gain remained associated with nonresponse after adjustment for collapsibility (odds ratio, 3.03 [1.16-7.88] per 1-standard deviation (SD) increase in loop gain [SD, 0.15]; P = 0.023).Conclusions: MAD nonresponders exhibit greater ventilatory instability, expressed as higher loop gain. Assessment of the baseline degree of ventilatory instability using this approach may improve upfront MAD treatment patient selection.Clinical trial registered with www.clinicaltrials.gov (NCT01532050).

0568 Physiologic OSA Traits and CPAP Adherence Among Patients with Coronary Artery Disease and OSA

Abstract Introduction Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), but adherence to continuous positive airway pressure (CPAP) in this population is poor. Low arousal threshold (ArTH), a pathophysiologic OSA trait, is associated with low rates of regular CPAP use in sleep clinic populations. We aimed to determine whether ArTH or other physiologic OSA traits (i.e. pharyngeal collapsibility, muscle compensation, loop gain) are associated with CPAP adherence in patients with CAD and OSA. Methods A secondary analysis of a randomized controlled trial of OSA treatment in patients with CAD (RICCADSA) was performed. OSA (apnea hypopnea index, AHI≥5/hour) was assessed by polysomnography. Arousal threshold (% eupneic ventilation, %Ve), loop gain (LG), pharyngeal collapsibility (%Ve) and compensation (%Ve) were estimated from polysomnography using a validated method. Adherence to auto-titrated CPAP (hours/night) was obtained from machine downloads at 1, 3, 6, 12 and 24 months. Mixed modelling was used to assess the association between OSA traits and CPAP adherence. Results Participants (n=262) were 64.1±7.9 years old, with BMI of 29.2±4.2 and 86% were men. The mean AHI was 40.8±23.6 events/hour with oxygen nadir of 81.3±7.1%. The median (IQR) CPAP adherence (hrs/night) was 3.0 (0.9, 5.8) at 1-mo and 3.0 (0.0, 5.6) at 24-mo. Compared to reference studies, the CAD patients exhibited an elevated LG 0.63 (0.53, 0.79), similar ArTH (%Ve) of 117.5% (106.5%, 136.4%), higher collapsibility (%Ve) at 90.1% (82.3%, 94.8%) and lower compensation (%Ve) at 3.7% (-0.7%, 8.7%).Only increasing pharyngeal muscle compensation was associated with lower CPAP adherence (β -0.04, p-value 0.048), effect modified by pharyngeal collapsibility (Compensation x Collapsibility, β &amp;lt;0.01, p-value 0.042). Conclusion In this group of patients with CAD, increasing muscle compensation was associated with lower CPAP adherence. Physiologic OSA traits may provide insight into prediction of CPAP adherence among patients with OSA and CAD. Support Zinchuk: Parker B. Francis Fellowship Program in Clinical Research. Sands: American Heart Association. Peker: Swedish Research Council, Swedish Heart-Lung Foundation.

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

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

The Effect of Upper Airway Surgery on Loop Gain in Obstructive Sleep Apnea

Controversy exists as to whether elevated loop gain is a cause or consequence of obstructive sleep apnea (OSA). Upper airway surgery is commonly performed in Asian patients with OSA who have failed positive airway pressure therapy and who are thought to have anatomical predisposition to OSA. We hypothesized that high loop gain would decrease following surgical treatment of OSA due to reduced sleep apnea severity. Polysomnography was performed preoperatively and postoperatively to assess OSA severity in 30 Chinese participants who underwent upper airway surgery. Loop gain was calculated using a validated clinically-applicable method by fitting a feedback control model to airflow. Patients were followed up for a median (interquartile range) of 130 (62, 224) days after surgery. Apnea-hypopnea index (AHI) changed from 60.8 (33.7, 71.7) to 18.4 (9.9, 42.5) events/h (P < .001). Preoperative and postoperative loop gain was 0.70 (0.58, 0.80) and 0.53 (0.46, 0.63) respectively (P < .001). There was a positive association between the decrease in loop gain and the improvement of AHI (P = .025). High loop gain was reduced by surgical treatment of OSA in our cohort. These data suggest that elevated loop gain may be acquired in OSA and may provide mechanistic insight into improvement in OSA with upper airway surgery. Registry: ClinicalTrials.gov, Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea, Identifier: NCT02696629, URL: https://clinicaltrials.gov/show/NCT02696629.

Assessing ventilatory control stability in children with and without an elevated central apnoea index.

Frequent central apnoeas are sometimes observed in healthy children; however; the pathophysiology of an elevated central apnoea index (CAI) is poorly understood. A raised CAI may indicate underlying ventilatory control instability (i.e. elevated loop gain, LG) or a depressed ventilatory drive. This pilot study aimed to compare LG in otherwise healthy children with an elevated CAI to healthy controls. Polysomnographic recordings from children (age > 6 months) without obstructive sleep apnoea and with a CAI > 5 events/h (n = 13) were compared with age and gender-matched controls with a CAI < 5 events/h (n = 13). Spontaneous sighs were identified during non-rapid eye movement (NREM) sleep, and breath-breath measurements of ventilation were derived from the nasal pressure signal. A standard model of ventilatory control (gain, time constant and delay) was used to calculate LG by transforming ventilatory fluctuations seen in response to a sigh into a ventilatory-drive signal that best matches observed ventilation. The high CAI group had an elevated LG (median = 0.36 (interquartile range, IQR = 0.35-0.53) vs 0.28 (0.23-0.36); P ≤ 0.01). There was no difference in either the time constant (P = 0.63) or delay (P = 0.29) between groups. Elevated LG observed in the high CAI group remained after accounting for degree of hypoxia (average oxygen saturation (SpO2 ) during each analysable window) experienced (0.40 (0.30-0.53) vs 0.25 (0.23-0.37); P = 0.04). An elevated CAI in otherwise healthy children is associated with a raised LG compared to matched controls with a low CAI, irrespective of level of hypoxia. This relative ventilatory instability helps explain the high CAI and may ultimately be able to help guide diagnosis and management in patients with high CAI.

Daytime loop gain is elevated in obstructive sleep apnea but not reduced by CPAP treatment.

Reduced ventilatory control stability (elevated loop gain) is a key nonanatomical, pathological trait contributing to obstructive sleep apnea (OSA), yet the mechanisms responsible remain unclear. We sought to identify the key factors contributing to elevated loop gain in OSA (controller vs. plant contributions) and to examine whether abnormalities in these factors persist after OSA treatment. In 15 males (8 OSA, 7 height, weight- and age -matched controls), we measured loop gain, controller gain, and plant gain using a pseudorandom binary CO2 stimulation method during wakefulness. Factors potentially influencing plant gain were also assessed (supine lung volume via helium dilution and spirometry). Measures were repeated 2 and 6 wk after initiating continuous positive airway pressure treatment. Loop gain (LG) was higher in OSA versus controls (LG at 1 cycle/min 0.28 ± 0.04 vs. 0.16 ± 0.04, P = 0.046, respectively), and the controller exhibited a greater peak response to CO2 and faster roll-off in OSA. OSA patients also exhibited reduced forced expiratory volume in the first second and forced vital capacity compared with controls (92.2 ± 1.7 vs. 102.9 ± 3.5% predicted, P = 0.021; 93.4 ± 3.1 vs. 106.6 ± 3.6% predicted, P = 0.015, respectively). There was no effect of treatment on any variable. These findings confirm loop gain is higher in untreated OSA patients than in matched controls; however, this was not affected by treatment. NEW & NOTEWORTHY Elevated loop gain contributes to obstructive sleep apnea (OSA) pathophysiology. However, whether loop gain is inherently elevated in OSA or induced by OSA itself, whether it is elevated due to increased chemoreflex sensitivity or obesity-dependent reduced lung volume, and whether it is treatment reversible, are all currently uncertain. This study found loop gain was elevated in OSA versus age-, sex-, height-, and weight-matched controls. However, this was not altered by 6-wk continuous positive airway pressure treatment.

Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy

A possible precision-medicine approach to treating obstructive sleep apnoea (OSA) involves targeting ventilatory instability (elevated loop gain) using supplemental inspired oxygen in selected patients. Here we test whether elevated loop gain and three key endophenotypic traits (collapsibility, compensation and arousability), quantified using clinical polysomnography, can predict the effect of supplemental oxygen on OSA severity.36 patients (apnoea-hypopnoea index (AHI) >20 events·h-1) completed two overnight polysomnographic studies (single-blinded randomised-controlled crossover) on supplemental oxygen (40% inspired) versus sham (air). OSA traits were quantified from the air-night polysomnography. Responders were defined by a ≥50% reduction in AHI (supine non-rapid eye movement). Secondary outcomes included blood pressure and self-reported sleep quality.Nine of 36patients (25%) responded to supplemental oxygen (ΔAHI=72±5%). Elevated loop gain was not a significant univariate predictor of responder/non-responder status (primary analysis). In post hoc analysis, a logistic regression model based on elevated loop gain and other traits (better collapsibility and compensation; cross-validated) had 83% accuracy (89% before cross-validation); predicted responders exhibited an improvement in OSA severity (ΔAHI 59±6% versus 12±7% in predicted non-responders, p=0.0001) plus lowered morning blood pressure and "better" self-reported sleep.Patients whose OSA responds to supplemental oxygen can be identified by measuring their endophenotypic traits using diagnostic polysomnography.

Breath-holding as a means to estimate the loop gain contribution to obstructive sleep apnoea.

A hypersensitive ventilatory control system or elevated "loop gain" during sleep is a primary phenotypic trait causing obstructive sleep apnoea (OSA). Despite the multitude of methods available to assess the anatomical contributions to OSA during wakefulness in the clinical setting (e.g. neck circumference, pharyngometry, Mallampati score), it is currently not possible to recognize elevated loop gain in patients in this context. Loop gain during sleep can now be recognized using simplified testing during wakefulness, specifically in the form of a reduced maximal breath-hold duration, or a larger ventilatory response to voluntary 20-second breath-holds. We consider that easy breath-holding manoeuvres will enable daytime recognition of a high loop gain in OSA for more personalized intervention. Increased "loop gain" of the ventilatory control system promotes obstructive sleep apnoea (OSA) in some patients and offers an avenue for more personalized treatment, yet diagnostic tools for directly measuring loop gain in the clinical setting are lacking. Here we test the hypothesis that elevated loop gain during sleep can be recognized using voluntary breath-hold manoeuvres during wakefulness. Twenty individuals (10 OSA, 10 controls) participated in a single overnight study with voluntary breath-holding manoeuvres performed during wakefulness. We assessed (1) maximal breath-hold duration, and (2) the ventilatory response to 20s breath-holds. For comparison, gold standard loop gain values were obtained during non-rapid eye movement (non-REM) sleep using the ventilatory response to 20s pulses of hypoxic-hypercapnic gas (6% CO2 -14% O2 , mimicking apnoea). Continuous positive airway pressure (CPAP) was used to maintain airway patency during sleep. Additional measurements included gold standard loop gain measurement during wakefulness and steady-state loop gain measurement during sleep using CPAP dial-ups. Higher loop gain during sleep was associated with (1) a shorter maximal breath-hold duration (r2 =0.49, P<0.001), and (2) a larger ventilatory response to 20s breath-holds during wakefulness (second breath; r2 =0.50, P<0.001); together these factors combine to predict high loop gain (receiver operating characteristic area-under-curve: 92%). Gold standard loop gain values were remarkably similar during wake and non-REM sleep. The results show that elevated loop gain during sleep can be identified using simple breath-holding manoeuvres performed during wakefulness. This may have implications for personalizing OSA treatment.

1129 Central Sleep Apnea after Hypoglossal Nerve Stimulation

The emergence of central sleep apnea has been reported when treating obstructive sleep apnea (OSA) with positive airway pressure (PAP), mandibular advanced devices (MAD) or upper airway surgery. We report the emergence of central sleep apnea following OSA treatment with hypoglossal nerve stimulation. A 61 -year-old male with a history of obesity (BMI 31.41) was diagnosed with moderate OSA (REI 27e/hr.). PAP therapy was attempted but not tolerated. An MAD did not improve his symptoms and a repeat portable sleep study with MAD continued to show an REI of 48.8e/hr. with obstructive and central events identified. (49 central apneas, 219 obstructive apneas, 36 hypopneas). A hypoglossal nerve stimulator was implanted after a drug induced endoscopy deemed him an appropriate candidate. Following activation, he completed an in-lab voltage titration up to (+-+) 1.2 V, however residual obstructive and central apneas were observed (AHI 24.71e/hr., 18 central apneas, 3 obstructive apneas, 124 hypopneas) with appearance of Cheyne-Stokes breathing. A follow up portable sleep study a month later continued to show obstructive and central events with an overall REI of 45e/hr. (25 central apneas, 119 obstructive apneas, 74 hypopneas). An awake endoscopy with advanced programming was performed which noted good response to stimulation at the tongue base, however poor response at the soft palate. His configuration was changed to (---) 0.6–1.6V. Follow up PSG titration with new settings demonstrated good control of OSA with an AHI of 2.08/hr. at 1V. Our patient developed central apneic events following implantation of a hypoglossal nerve stimulator for the treatment of obstructive sleep apnea. The pathophysiology behind this phenomenon may be explained by: 1) An unresolved obstruction which may have led to microarousals and overshoot of PaCO2 reduction below the apneic threshold during sleep. 2) Some patients with severe OSA may have an elevated loop gain which may be unmasked after inspiratory flow limitation is relieved, leading to central apneic events. These events eventually may disappear with continuous OSA treatment and eventual resetting of CO2 receptors. In our patient, central apneas resolved following advanced programming which optimized upper airway patency.

0508 SLEEP APNEA AND ATRIAL FIBRILLATION - PHENOTYPE AND OUTCOMES

Sleep apnea, especially central (CSA), is associated with atrial fibrillation (AF). We hypothesized that AF patients are at high risk for treatment-emergent/complex apnea, and residual disease during long-term therapy with positive airway pressure. The sleep laboratory database at the Beth Israel Deaconess Medical center and affiliated services was queried, focusing on patients with AF, to extract polysomnographic information. The BIDMC Online Medical Records was used to collect co-morbid information. Residual apnea and related information was extracted from the EnocreAnywhere database; at the BIDMC, tracking is life-long, enabling assessment of outcomes beyond 6 months. Three hundred and eighteen patients had complete clinical/polysomnographic data, and 212 were reviewed in EncoreAnywhere. Split night was 31%. Summary statistics: age 68.3 ± 11.1 years, 69.1% male, BMI 33.6 ± 8 Kg/M2, ejection fraction 53.5 ± 10.8 (22% less than 50%), hypertension 68.6%. Baseline total sleep time (TST): 181.4 ± 116.3 minutes, sleep efficiency 62.9 ± 19.3 %, N1 24.3 ± 21.5% TST, N3: 9.7 ± 13.9 % TST, RDI: 39.4 ± 21.7, AHI4% 8.2 ± 11.9, minimum saturation 81.8 ± 10 %. Titration data: TST: 242 ± 98.9 minutes, sleep efficiency 66.9 ± 19.8 %, N1: 18 ± 15.2 %, RDI 27 ± 21.6, AHI4% 5 ± 8.5, minimum saturation 85.4 ± 6.9 %. CSA was noted in 4% on baseline, and treatment-emergent/complex apnea in 30%. The mean duration of use of positive airway pressure (93% continuous) was 21 ± 3 months, mean use 4.1 ± 2.1 hours. Residual AHI-flow was 11.6 ± 7.8 / hour of use, and periodic breathing of at least 10 minutes duration on visual waveforms inspection in 76.4 %. Patients with AF have highly fragmented sleep during diagnostic and titration polysomnograms. Complex sleep apnea is common, as is residual sleep apnea and periodic breathing on waveforms. This likely reflects persistently elevated loop gain. AF patients with sleep apnea are at high risk for reduced treatment effectiveness, and may require a dedicated phenotype-driven clinical pathway for optimal management. Beth Israel Deaconess Medical Center Chief Academic Officer’s Innovation Grant.

The Combination of Supplemental Oxygen and a Hypnotic Markedly Improves Obstructive Sleep Apnea in Patients with a Mild to Moderate Upper Airway Collapsibility.

Obstructive sleep apnea (OSA) results from the interaction of several physiological traits; specifically a compromised upper airway anatomy and muscle function, and two key non-anatomical deficits: elevated loop gain and a low arousal threshold. Although continuous positive airway pressure (CPAP) is an efficacious treatment, it is often poorly tolerated. An alternative approach could involve administering therapies targeting the non-anatomic causes. However, therapies (oxygen or hypnotics) targeting these traits in isolation typically improve, but rarely resolve OSA. Therefore, our aim was to determine how the combination of oxygen and eszopiclone alters the phenotypic traits and OSA severity and to assess the baseline phenotypic characteristics of responders/nonresponders to combination therapy. In a single-blinded randomized crossover study, 20 OSA patients received combination therapy (3 mg eszopiclone and 40% oxygen) versus placebo/sham air, with 1 w between conditions. Under each condition, we assessed the effects on OSA severity (clinical polysomnography) and the phenotypic traits causing OSA using CPAP manipulations (research polysomnography). Combination therapy reduced the apnea-hypopnea index (51.9 ± 6.2 vs. 29.5 ± 5.3 events/h; P < 0.001), lowered both the ventilation associated with arousal (5.7 ± 0.3 vs. 5.2 ± 0.3 L/min; P = 0.05) and loop gain (3.3 ± 0.5 vs. 2.2 ± 0.3; P = 0.025). Responders to therapy (apnea-hypopnea index reduced by > 50% to below 15 events/h; n = 9/20) had less severe OSA (P = 0.001), a less collapsible upper airway (P = 0.01) and greater upper airway muscle effectiveness (P = 0.002). The combination of lowering loop gain and raising the arousal threshold is an effective therapy in patients whose anatomy is not severely compromised. Our work demonstrates that combining therapies that target multiple traits can resolve OSA in selected individuals. ClinicalTrials.gov, ID: NCT01633827.

Pathogenesis of central and complex sleep apnoea.

Central sleep apnoea (CSA) - the temporary absence or diminution of ventilatory effort during sleep - is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne-Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, that is elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via continuous positive airway pressure (CPAP), tracheostomy or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep-wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, that is low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, for example CPAP improves lung volume (plant gain), stimulants reduce the alveolar-inspired PCO2 difference and supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalized interventions for CSA.

Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.

Elevated loop gain, consequent to hypersensitive ventilatory control, is a primary nonanatomical cause of obstructive sleep apnoea (OSA) but it is not possible to quantify this in the clinic. Here we provide a novel method to estimate loop gain in OSA patients using routine clinical polysomnography alone. We use the concept that spontaneous ventilatory fluctuations due to apnoeas/hypopnoeas (disturbance) result in opposing changes in ventilatory drive (response) as determined by loop gain (response/disturbance). Fitting a simple ventilatory control model (including chemical and arousal contributions to ventilatory drive) to the ventilatory pattern of OSA reveals the underlying loop gain. Following mathematical-model validation, we critically tested our method in patients with OSA by comparison with a standard (continuous positive airway pressure (CPAP) drop method), and by assessing its ability to detect the known reduction in loop gain with oxygen and acetazolamide. Our method quantified loop gain from baseline polysomnography (correlation versus CPAP-estimated loop gain: n=28; r=0.63, p<0.001), detected the known reduction in loop gain with oxygen (n=11; mean±sem change in loop gain (ΔLG) -0.23±0.08, p=0.02) and acetazolamide (n=11; ΔLG -0.20±0.06, p=0.005), and predicted the OSA response to loop gain-lowering therapy. We validated a means to quantify the ventilatory control contribution to OSA pathogenesis using clinical polysomnography, enabling identification of likely responders to therapies targeting ventilatory control.

Rebuttal from J. E. Orr, B. A. Edwards and A. Malhotra.

Younes and others have pioneered our understanding of loop gain (LG) in obstructive sleep apnoea (Younes et al. 2001). On his side of the argument, Younes eloquently differentiates between the ‘chemical’ LG of the respiratory control system and the ‘net LG’, which is an upper airway modulated chemical LG. We agree with this differentiation, as well as most of the arguments provided by our colleague. In fact, the only thing we disagree with is how the (limited) data addressing chemical LG as a cause is interpreted. At sleep onset, upper airway resistance increases due to upper airway collapse yielding CO2 increases as determined by plant gain. Hypercapnia will increase ventilatory drive as determined by controller gain. Increasing drive will eventually trigger arousal, and the cycle repeats. Thus, chemical LG (defined here as the product of controller and plant gain) must be a critical factor responsible for causing an individual's obstructive sleep apnoea (OSA). We currently treat OSA by preventing the initial increase in upper airway resistance with continuous positive airway pressure (CPAP). Alternatively, we could attenuate CO2 increases during respiratory events (i.e. acetazolamide) or increases in respiratory drive (i.e. oxygen). Both would be predicted to reduce an individual's propensity towards developing OSA. For a patient to develop OSA in the first place, they must have some degree of anatomical susceptibility; therefore, we view OSA as caused by ‘vulnerable’ upper airway anatomy/collapsibility, with the non-anatomical traits being thought of as ‘effect modifiers’ that dictate whether or not an individual develops OSA (Fig. ​(Fig.1).1). Considering LG as an effect modifier helps explain why treatments to reduce LG (i.e. oxygen or acetazolamide) often improve OSA in some but not all patients. The fact that OSA is not completely resolved with such therapies suggests that an elevated LG is not the only factor causing OSA. Recent data suggest that 23% of OSA patients have a highly collapsible upper airway, such that a high or low LG may be irrelevant (Eckert et al. 2013). However, the majority of patients have an airway in the intermediate range, where factors such as LG will affect the development of OSA. Therefore an elevated chemical LG is important in OSA pathogenesis in some patients. We hope that the current debate has produced a large enough disturbance in the research community to stimulate the appropriate response, i.e. future research in this area. Figure 1 Role of the non-anatomical traits in the pathogenesis of obstructive sleep apnoea

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea.

CrossTalk opposing view: Loop gain is not a consequence of obstructive sleep apnoea.