The double loop gain in obstructive sleep apnea syndrome

Current Respiratory Medicine Reviews, 2007

There is a close relationship among the types of sleep apnea (central, obstructive, and mixed) in regard to both the pathogenesis and in the clinical management of sleep apnea syndromes. This review will recount the rationale for the use of animal models in understanding intermediate traits, such as the ventilatory responses to hypoxia and reoxygenation, seen with human sleep apnea. One feature of particular interest will be the dynamic responses of the control system, specifically the instability over time that could operate to produce repetitive apneas. The recurrent nature of clinically significant sleep apnea can be understood in terms of feedback control, or "loop gain". We will discuss findings in a mouse model for recurrent apneas and propose that there exist genetic mechanisms that could determine loop gain in the respiratory control system.

IEEE Transactions on Biomedical Engineering, 2002

Previous studies on ventilatory control in obstructive sleep apnea (OSA) have generally indicated depressed chemosensitivity, implying greater stability of the chemical control of breathing in these subjects. However, these results were based on tests involving steady-state or quasi-steady measurements obtained in wakefulness. We have developed a method for assessing the dynamic stability characteristics of chemoreflex control in OSA patients during sleep. While continuous positive airway pressure was applied to stabilize the upper airways, acoustically stimulated arousals were used to perturb the respiratory system during sleep. The fluctuations in esophageal pressure that ensued were analyzed, using a closed-loop minimal model, to estimate the chemoreflex loop impulse response (CLIR). Tests using simulated data confirmed the validity of our estimation algorithm. Application of the method to arousal responses measured in six OSA and five normal subjects revealed no statistically significant differences in gain margins and loop gain magnitudes between the two groups. However, the CLIR in the OSA subjects exhibited faster and more oscillatory dynamics. This result implies that, in addition to unstable upper airway mechanics, an underdamped chemoreflex control system may be another important factor that promotes the occurrence of periodic obstructive apneas during sleep.

The European respiratory journal, 2015

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 quan...

Journal of Applied Physiology, 2007

The response to chemical stimuli (chemical responsiveness) and the increases in respiratory drive required for arousal (arousal threshold) and for opening the airway without arousal (effective recruitment threshold) are important determinants of ventilatory instability and, hence, severity of obstructive apnea. We measured these variables in 21 obstructive apnea patients (apnea-hypopnea index 91 ± 24 h−1) while on continuous-positive-airway pressure. During sleep, pressure was intermittently reduced (dial down) to induce severe hypopneas. Dial downs were done on room air and following ≈30 s of breathing hypercapneic and/or hypoxic mixtures, which induced a range of ventilatory stimulation before dial down. Ventilation just before dial down and flow during dial down were measured. Chemical responsiveness, estimated as the percent increase in ventilation during the 5th breath following administration of 6% CO2 combined with ≈4% desaturation, was large (187 ± 117%). Arousal threshold, ...

CHEST Journal, 2011

O bstructive sleep apnea syndrome (OSAS) is a major public health problem with a prevalence estimated at approximately 4% of adults in both Western and Asian countries. 1,2 Nasal continuous positive airway pressure (CPAP) therapy for OSAS has been the most effective and widely used treatment. However, approximately 25% to 50% of patients with OSA will either refuse to try or will not tolerate CPAP therapy. 6 Furthermore, some patients do not respond to CPAP treatment, either without symptom improvements or without reductions in overall respiratory events. Finally, central apneas can emerge with initiation of CPAP therapy, a condition that has been called "complex sleep apnea." 7 Taken together, these facts indicate signifi cant variability of the OSAS phenotype.

Journal of Sleep Research

SummaryObstructive sleep apnea is linked to cardiovascular disease, metabolic disorders and dementia. The precise nature of the association between respiratory events in obstructive sleep apnea, cortical or subcortical arousals, and cognitive, autonomic and oxidative stress consequences remains incompletely elucidated. Previous studies have aimed to understand the relationship between obstructive sleep apnea and arousal patterns, as defined by the cyclic alternating pattern, but results have been inconsistent, in part likely due to the presence of associated comorbidities. To better define this relationship, we analysed cyclic alternating patterns in patients with obstructive sleep apnea without any additional comorbidities. We identified 18 adult male, non‐obese subjects with obstructive sleep apnea and no other comorbidities or medication history, who underwent whole‐night electroencephalography and polysomnography. Cyclic alternating pattern analysis was performed and verified by...

Journal of Applied Physiology, 2011

There is not a clinically available technique for measuring the physiological traits causing obstructive sleep apnea (OSA). Therefore, it is often difficult to determine why an individual has OSA or to what extent the various traits contribute to the development of OSA. In this study, we present a noninvasive method for measuring four important physiological traits causing OSA: 1) pharyngeal anatomy/collapsibility, 2) ventilatory control system gain (loop gain), 3) the ability of the upper airway to dilate/stiffen in response to an increase in ventilatory drive, and 4) arousal threshold. These variables are measured using a single maneuver in which continuous positive airway pressure (CPAP) is dropped from an optimum to various suboptimum pressures for 3- to 5-min intervals during sleep. Each individual's set of traits is entered into a physiological model of OSA that graphically illustrates the relative importance of each trait in that individual. Results from 14 subjects (10 w...

Instable ventilatory control is an endotypic trait of obstructive sleep apnea syndrome (OSAS). The study aimed to evaluate the relationships between the anatomical compromise of the upper (oro- and naso-pharynx) and lower airways and ventilatory control (measured by chemical loop gain) in otherwise healthy children suffering from moderate to severe OSAS (apnea hypopnea index ≥ 5/hour). The children underwent ear, nose and throat examination, measurement of impedance of the respiratory system that allowed characterizing peripheral lung mechanics using the extended Resistance-Inertance-Compliance model. Physiologically constrained analytical model based on tidal breathing analysis allowed the computation of steady-state plant gain (PG0), steady-state controller gain (CG0) and steady-state loop gain (LG0). Medium-frequency components of feedback control system were then deduced. Fifty children (median age 11.2 years, 17 females) were enrolled. Oropharyngeal obstruction was associated w...

Rationale: Current scoring criteria of non-apneic events (ie, hypopnea) require the presence of oxyhemoglobin desaturation and/or arousal. However, other sleep study parameters may help to identify abnormal respiratory events (REs) and assist in making more accurate diagnosis. Objectives: To investigate whether non-apneic REs without desaturation or cortical arousal are associated with respiratory and cardiac consequences. Methods: Thirteen participants with sleep disturbances (snoring and/or excessive day time sleepiness), were screened using attended in laboratory pol-ysomnography (PSG) while monitoring pressure and airflow via a nasal mask with an attached pneumotach. To separate the contribution of the upper airway resistance (R UA) and total pulmonary resistance (R L), supraglottic and esophageal pressures were measured using Millar pressure catheters. R L and R UA were calculated during baseline and hypopneas. R L was defined as the resistive pressure divided by the maximal flow during inspiration and expiration. Hypopnea was defined 30% decrease in flow with 3% desaturation and/or cortical arousal. REs was defined as 30% decrease in the flow without desaturation and/or cortical arousal. In eight subjects continuous positive airway pressure (CPAP) was titrated to optimal pressure. R-R interval (RRI) was defined as consecutive beat-to-beat intervals on single lead electrocardiograph (ECG) during baseline, RE/hypopnea and on optimal CPAP. Results: REs associated with increased expiratory R UA (14.6 ± 11.3 vs. 7.5 ± 4.5 cmH 2 O L −1 s −1 ; p < .05), and increased expiratory R L relative to baseline (29.2 ± 14.6 vs. 20.9 ± 11.0 and 23.7 ± 12.1 vs. 14.3 ± 5.6 cmH 2 O L −1 s −1 during inspiration and expiration, respectively; p < .05). RRI decreased significantly following RE and hypopnea relative to baseline (804.8 ± 33.1 vs. 806.4 ± 36.3 vs. 934.3 ± 45.8 ms; p < .05). Optimal CPAP decreased expiratory R UA (4.0 ± 2.5 vs. 7.5 ± 4.5 cmH 2 O L −1 s −1 ; p < .05), decreased inspiratory R L (12.6 ± 14.1 vs. 7.5 ± 4.5 cmH 2 O L −1 s −1 ; p < .05), and allowed RRI to return to baseline (p < .05). RRI dips index was an independent predictor of sleep-disordered breathing (SDB) when non-apneic REs were accounted for in symptomatic patients (p < .05). Conclusions: Non-apneic REs without cortical arousal or desaturation are associated with significant respiratory and heart rate changes. Optimal CPAP and the reduction of resistive load are associated with the normalization of heart rate indicating potential clinical benefit.

Encyclopedia of Religion and War (1st ed.). New York: Berkshire/Routledge, 2004, 342-347, 2004