Increase In Loop Gain Research Articles

Sex-specific Age-Related Worsening of Pathological Endotypic Traits in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is more prevalent in men and older adults. Few studies have explored variations in pathological endotypic traits by age and sex using a large patient sample, offering insights into the development of the disease. Our study aims to examine how endotype characteristics of obstructive sleep apnea vary across age in different sex. A cross-sectional study was conducted, enrolling 2296 adult patients referred for in-laboratory diagnostic polysomnography at a single sleep center in Taiwan. Among them, 1374 had an apnea-hypopnea index ≥ 5. Using the "Phenotyping Using Polysomnography" method, we estimated four endotypic traits-arousal threshold, upper airway collapsibility, loop gain, and upper airway muscle compensation. Demographic and polysomnographic characteristics were compared between sexes and age groups. Generalized linear regression and generalized additive models were employed to explore the associations of sex and age with endotypic traits. Men with OSA exhibited higher collapsibility and lower compensation than women (difference: 4.32 %eupnea and 4.49 %eupnea, respectively). Younger patients with OSA had a higher prevalence of obesity, more snoring symptoms, and lower loop gain compared to older patients. For men, age was correlated with increased collapsibility, increased loop gain, and decreased arousal threshold after 37 years old. Whereas in women, endotypic traits were not associated with age, except for an increase in loop gain with advancing age. Personalized treatment options for OSA should take into consideration age and sex. Reducing loop gain could be a treatment objective for older patients with OSA.

Identifying the pathophysiological traits of obstructive sleep apnea during dexmedetomidine sedation.

Dexmedetomidine (DEX) has been described as a safe sedative in clinical practice, but its effects on the pathophysiological traits of obstructive sleep apnea (OSA) are unclear. We estimated the effects of DEX sedation on the four key pathophysiological traits of OSA (pharyngeal collapsibility, dilator muscle function, arousal threshold, and loop gain) in adult patients with OSA by conducting a secondary analysis of a prospective diagnostic trial. Pathophysiological traits estimated from polysomnography and the respiratory parameters under natural sleep and DEX-induced sleep were compared. Bivariate and multivariate linear regression analyses were used to estimate the relationship between pathophysiological traits and OSA severity for both sleep states. Adult patients with OSA had a significantly higher pharyngeal collapsibility (Vpassive: 44.9 [15.7 to 53.8] vs. 53.3 [34.2 to 66.3] %eupnea, p < 0.001), arousal threshold (178.5 [132.5 to 234.6] vs. 140.5 [123.2 to 192.3] %eupnea, p < 0.001), and loop gain (LG1: 0.74 ± 0.25 vs. 0.60 ± 0.17, p < 0.001; LGn: 0.52 ± 0.12 vs. 0.44 ± 0.08, p < 0.001) during DEX-induced sleep compared with natural sleep. There was no significant difference in dilator muscle function or PSG respiratory parameters between natural versus DEX-induced sleep states. Bivariate regression analysis showed varying degrees of correlation between OSA traits and severity. Multiple regression analysis indicated that collapsibility was the strongest predictor of the apnea-hypopnea index for both sleep states. Dexmedetomidine sedation in patients with OSA increased the pharyngeal collapsibility without impairing dilator muscle function, while elevating arousal threshold and increasing loop gain.

The Combination of Betahistine and Oxybutynin Increases Respiratory Control Sensitivity (Loop Gain) in People with Obstructive Sleep Apnea: A Randomized, Placebo-Controlled Trial.

RationaleThere are widespread histaminergic projections throughout the brain, including hypoglossal nuclei, that modulate pharyngeal muscle tone and respiratory control. Hence, histaminergic stimulation pharmacologically may increase pharyngeal muscle tone and stabilize respiratory control (loop gain) to reduce obstructive sleep apnea (OSA) severity. Antimuscarinics also increase REM pharyngeal muscle tone in rats. Thus, a combination of histaminergic and anti-muscarinic drugs may be a novel target for OSA pharmacotherapy. However, this has not been investigated. Accordingly, we aimed to test the effects of betahistine (Beta), an H3-autoreceptor antagonist which thereby increases histamine levels, in combination with the antimuscarinic oxybutynin (Oxy), on OSA severity, OSA endotypes, polysomnography parameters and next-day sleepiness and alertness.MethodsThirteen adults with OSA received either Beta-Oxy (96–5mg) or placebo according to a randomized, crossover, double-blind design, prior to polysomnography. Participants completed the Karolinska Sleep Scale and Leeds Sleep Evaluation Questionnaire and a driving simulation task to quantify next-day sleepiness and alertness. OSA endotypes were estimated through validated algorithms using polysomnography.ResultsCompared to placebo, Beta-Oxy increased respiratory control sensitivity (loop gain) (0.52[0.24] vs 0.60[0.34], median [IQR], P = 0.021) without systematically changing OSA severity (34.4±17.2 vs 40.3±27.3 events/h, mean±SD, P = 0.124), sleep efficiency, arousal index or markers of hypoxemia. Beta-Oxy was well tolerated and did not worsen next-day sleepiness/alertness.ConclusionRather than stabilize breathing during sleep, Beta-Oxy increases loop gain, which is likely to be deleterious for most people with OSA. However, in certain conditions characterized by blunted respiratory control (eg, obesity hypoventilation syndrome), interventions to increase loop gain may be beneficial.

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).

Apnea-hypopnea index is associated with increased loop gain during sleep at ascending altitudes

Apnea-hypopnea index is associated with increased loop gain during sleep at ascending altitudes

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea.

Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery of respiratory and limb motor dysfunction. One possible side-effect of this therapy is an increase in apnoeic event number and duration, which is particularly relevant to participants with motor disorders coupled with an increased incidence of sleep apnoea. In this study, we report that increases in apnoeic event number and duration, following exposure to daily intermittent hypoxia, are the result of an increase in respiratory loop gain and the arousal threshold, in participants with obstructive sleep apnoea. Daily exposure to mild intermittent hypoxia also led to an increase in the ventilatory response to arousal. Accordingly, individuals with motor disorders receiving mild intermittent hypoxia as a therapy should be screened for the presence of sleep apnoea, and if present, administration of intermittent hypoxia during hours of wakefulness should be combined with continuous positive airway pressure treatment during sleep. We determined if exposure to mild intermittent hypoxia (MIH) causes an increase in loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. Male participants with obstructive sleep apnoea (apnoea-hypopnoea index >5events/h), matched for age, body mass index and race were divided into two groups (n=13 in each group). Following a baseline sleep study, one group was exposed to twelve 4-min episodes of hypoxia each day for 10days and the other group to a sham protocol (SP). On Days 1 and 10, a sleep study was completed following exposure to MIH or the SP. For each sleep study, LG and the AT were measured during NREM sleep, using a model-based approach, and expressed as a fraction of baseline measures. LG increased after exposure to MIH (Day 1: 1.11±0.03, P=0.002, Day 10: 1.17±0.05, P=0.001), but not after the SP (Day 1: 1.03±0.04, P=1.0, Day 10: 1.0±0.02, P=1.0). AT also increased after exposure to MIH (Day 1: 1.13±0.05, P=0.01, Day 10: 1.19±0.08, P=0.05) but not after the SP (Day 1: 1.04±0.05, P=0.6, Day 10: 0.96±0.04, P=1.0). Our results might account for increases in apnoea frequency and duration previously observed during NREM sleep following exposure to MIH. Our results also have implications for the use of MIH as a therapeutic modality.

Chapter 22 - Clinical neurophysiology of apnea

Understanding the clinical neurophysiology of apnea generation encompasses discussion of the neuroanatomic aspects of central respiratory rhythm and pattern generation, including the central respiratory control networks, central and peripheral chemoreceptors, mechanisms of respiratory muscles, and sleep state dependent differences. Anatomical and functional links to apnea also involve central respiratory motor output recruited from the hypoglossal nerve, which has led to novel treatments for obstructive sleep apnea. Autonomic fluctuations occur in relation to sleep-wake and sleep states (i.e., REM vs NREM sleep), with both parasympathetic and sympathetic contributions. Finally, our understanding of the pathophysiology of obstructive sleep apnea now includes concepts of critical closing pressure of the upper airway, increased loop gain as reflected by high responsiveness to external perturbations, inadequate responsiveness of upper airway muscle recruitment, and reductions in arousal threshold leading to ventilatory instability. In turn, these concepts have led to the development of novel therapies such as hypoglossal nerve stimulation and targeting key culprit physiologic mechanisms specific to the individual.

Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure

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 CO2 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. 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. 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 CO2 stimulation. 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). 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.

Congestive Heart Failure and Central Sleep Apnea.

Congestive heart failure (CHF) is among the most common causes of admission to hospitals in the United States, especially in those over age 65. Few data exist regarding the prevalence CHF of Cheyne-Stokes respiration (CSR) owing to congestive heart failure in the intensive care unit (ICU). Nevertheless, CSR is expected to be highly prevalent among those with CHF. Treatment should focus on the underlying mechanisms by which CHF increases loop gain and promotes unstable breathing. Few data are available to determine prevalence of CSR in the ICU, or how CSR might affect clinical management and weaning from mechanical ventilation.

Central Sleep Apnea at High Altitude.

The discovery of central sleep apnea (CSA) at high altitude is usually attributed to Angelo Mosso who published in 1898. It can occur in susceptible individuals at altitude above 2000 m, but at very high altitude, say above 5000 m, it will occur in most subjects. Severity is correlated with ventilatory responsiveness, particularly to hypoxia. Theoretically, it should spontaneously improve with time and acclimatization. Although the time course of resolution is not well described, it appears to persist for more than a month at 5000 m.It occurs due to the interaction of hypocapnia with stages 1 and 2 NREM sleep, in the presence of increased loop-gain. The hypocapnia is secondary to hypoxic ventilatory drive. With acclimatization, one might expect that the increase in PaO2 and cerebral blood flow (CBF) would mitigate the CSA. However, over time, both the hypoxic and hypercapnic ventilatory responses increase, causing an increase in loop gain which is a counteracting force.The severity of the CSA can be reduced by descent, supplemental oxygen therapy, oral or intravenous acetazolamide. Recent studies suggest that acute further increases in cerebral blood flow will substantially, but temporarily, reduce central sleep apnea, without altering acid based balance. Very recently, bi-level noninvasive ventilation has also been shown to help (mechanism unknown). Sleep quality can be improved independent of the presence of CSA by the use of benzodiazepine sedation.

Tailored treatment strategies for obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by repetitive collapse of the upper airway (UA) during sleep and is associated with chronic intermittent hypoxemia, catecholamine surges, and sleep disrupt. Multiple pathophysiological risk factors have been identified and contribute to OSA, including anatomical abnormalities (elevated UA mechanical load), compromised UA dilators, increased loop gain (unstable respiratory control), and decreased arousal threshold. These factors may contribute to the pathophysiology of sleep apnea in different individuals and recent evidence suggests that treatment may be targeted towards underlying pathophysiological mechanism. In some cases, combination therapy may be required to treat the condition.

Model-based estimation of loop gain using spontaneous breathing: A validation study

Non-invasive assessment of ventilatory control stability or loop gain (which is a key contributor in a number of sleep-related breathing disorders) has proven to be cumbersome. We present a novel multivariate autoregressive model that we hypothesize will enable us to make time-varying measurements of loop gain using nothing more than spontaneous fluctuations in ventilation and CO2. The model is adaptive to changes in the feedback control loop and therefore can account for system non-stationarities (e.g. changes in sleep state) and it is resistant to artifacts by using a signal quality measure. We tested this method by assessing its ability to detect a known increase in loop gain induced by proportional assist ventilation (PAV). Subjects were studied during sleep while breathing on continuous positive airway pressure (CPAP) alone (to stabilize the airway) or on CPAP+PAV. We show that the method tracked the PAV-induced increase in loop gain, demonstrating its time-varying capabilities, and it remained accurate in the face of measurement related artifacts. The model was able to detect a statistically significant increase in loop gain from 0.14±10 on CPAP alone to 0.21±0.13 on CPAP+PAV (p<0.05). Furthermore, our method correctly detected that the PAV-induced increase in loop gain was predominantly driven by an increase in controller gain. Taken together, these data provide compelling evidence for the validity of this technique.

Rebuttal from Magdy Younes.

There is really little disagreement in the two accounts (Orr et al. 2014; Younes, 2014) if one considers that I addressed the increase in loop gain (LG) when the upper airway (UA) is unstable (hereafter called Actual LG) whereas Orr et al. addressed only that component of LG that is measured when UA is stabilized, the component I called Chemical LG. To put these two loop gains in the proper perspective I refer to several investigations from the laboratory of the opposing authors. Wellman et al. (2011) and Edwards et al. (2012) measured the Actual LG in obstructive sleep apnoea (OSA) patients by relating the increase in ventilation at airway opening to the reduction in ventilation during the event. The values reported ranged from 1.4 to 14.0 (average 4.4). This is an order of magnitude greater than the Chemical LG (∼0.4; Younes et al. 2001; Wellman et al. 2004, 2008; Jordan et al. 2005). As indicated earlier (Younes, 2014), this difference results from an increased delay in getting a ventilatory response because the airway refuses to open until a threshold chemical drive, the ‘effective recruitment threshold’, is reached (Younes et al. 2007, 2012). Clearly, this increase in LG is a consequence of OSA. What is called a high LG in the absence of UA instability, and what is emphasized as a cause of OSA by Orr et al. is a Chemical LG of 0.7 with a maximum of 0.9 (Wellman et al. 2008). Even this relatively small increase in Chemical LG is the result of untreated OSA since it disappears with treatment (Loewen et al. 2009; Salloum et al. 2010). Orr et al. argue that this modest increase nonetheless contributes to the severity of OSA. I have no problem with this, and have in fact indicated so in my article (Younes, 2014). However, I believe that Orr et al. have exaggerated this clinical importance. They cite two papers in support of effectiveness of oxygen. The paper by Chowdhuri et al. (2010) simply demonstrated a reduction, with oxygen, in hypocapnic ventilatory response to CO2 in normal subjects. The study by Wellman et al. (2008) found >50% reduction in the apnoea–hypopnoea index (AHI) when breathing oxygen in only three out of six patients selected from a base of 43 patients because they had a high LG (range 0.4–0.9). Some of this AHI reduction was due to prolongation of apnoeic events and to disappearance of central/mixed events, which contributed ∼15% of baseline events. Thus the number of true obstructive events that were eliminated by oxygen must have been small. The acetazolamide evidence is also quite unconvincing. The 2013 study by Edwards et al. did not address the severity of OSA. In the 2012 study by Edwards et al. acetazolamide caused a reduction in AHI in patients already treated by continuous positive airway pressure (CPAP) and in whom Chemical LG was probably normal (Loewen et al. 2009; Salloum et al. 2010). So, it is not possible to attribute the improvement in AHI to a reduction in Chemical LG. It is important to note that both acetazolamide (Edwards et al. 2012) and oxygen breathing (Chowdhuri et al. 2010) increase baseline ventilation, and hence respiratory drive. Their helpful effects in some patients need not reflect a reduction in Chemical LG but may be because chemical drive needs to increase less to reach the effective recruitment threshold for UA opening.

Alternative approaches to treatment of Central Sleep Apnea.

Divergent approaches to treatment of hypocapnic central sleep apnea syndromes reflect the difficulties in taming a hyperactive respiratory chemoreflex. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable non-rapid eye movement (NREM) sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient dyssynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Provent and Winx may be less likely to trigger central apneas or periodic breathing in those with a narrow CO2 reserve. An oral appliance can meaningfully reduce positive pressure requirements and thus enable treatment of complex apnea. Novel pharmacological approaches may target mediators of carotid body glomus cell excitation, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is not always successful, and multi-modality therapy might need to be considered. Phenotyping of sleep apnea beyond conventional scoring approaches is the key to optimal management.

Complex Sleep Apnea

Complex sleep apnea currently refers to the emergence and persistence of central apneas and hypopneas following the application of positive airway pressure therapy in patients with obstructive sleep apnea. However, this narrow definition is an "outcome" and does not capture the spectrum of pathological activation of the respiratory chemoreflex in sleep apnea. The International Classification of Sleep Disorders - 3rd edition recognizes the phenomenon of Treatment-Related Central Sleep Apnea, but the phenotype is usually evident prior to onset of therapy. The key polysomnographic characteristics of chemoreflex modulated and mediated sleep apnea are nonrapid eye movement (NREM) dominance of respiratory events, short (<30seconds) or long (>60seconds) cycle time with a self-similar metronomic timing, and spontaneous improvement during rapid eye movement (REM) sleep. Thus, the majority of chemoreflex effects go unrecognized due to the bias toward obstructive sleep apnea's current scoring criteria. Any treatment of apparently obstructive sleep apnea, including surgery and oral appliances, can expose chemoreflex-driven instabilities. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable NREM sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient desynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Novel pharmacological approaches may target mediators of carotid body hypoxic sensitization, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is unlikely to be successful, and the power of multi-modality therapy should be harnessed for optimal outcomes.

The effect of partial acclimatization to high altitude on loop gain and central sleep apnoea severity

Loop gain is an engineering term that predicts the stability of a feedback control system, such as the control of breathing. Based on earlier studies at lower altitudes, it was hypothesized that acclimatization to high altitude would lead to a reduction in loop gain and thus central sleep apnoea (CSA) severity. This study used exposure to very high altitude to induce CSA in healthy subjects to investigate the effect of partial acclimatization on loop gain and CSA severity. Measurements were made on 12 subjects (age 30 ± 10 years, body mass index 22.8 ± 1.9, eight males, four females) at an altitude of 5050 m over a 2-week period upon initial arrival (days 2-4) and following partial acclimatization (days 12-14). Sleep was studied by full polysomnography, and resting arterial blood gases were measured. Loop gain was measured by the 'duty cycle' method (duration of hyperpnoea/cycle length). Partial acclimatization to high-altitude exposure was associated with both an increase in loop gain (duty cycle fell from 0.60 ± 0.05 to 0.55 ± 0.06 (P = 0.03)) and severity of CSA (apnoea-hypopnoea index increased from 76.8 ± 48.8 to 115.9 ± 20.2 (P = 0.01)), while partial arterial carbon dioxide concentration fell from 29 ± 3 to 26 ± 2 (P = 0.01). Contrary to the results at lower altitudes, at high-altitude loop gain and severity of CSA increased.

SELF-OSCILLATING CLASS D AMPLIFICATION DEVICE

An amplification device, comprising a device input receiving a device input signal, an amplifier unit comprising a zero crossing detector unit, an output filter and a lead-lag compensation network. The zero crossing detector unit compares the device input signal with a reference potential and switches a pulse width modulated detector output signal between first and second voltage levels dependent on the comparison. The amplifier unit provides an actual device output signal, e.g., an amplified representation of the device input signal. The amplification device further comprises a device output providing the actual device output signal, a control loop bridging the amplifier unit and comprising a forward filter, e.g., an integrating filter, for increasing loop gain improving the signal-to-noise ratio of the actual device output signal, and a deviation detection unit detecting over modulation of the amplifier unit, so that the amplification device disables forward filter functioning upon over modulation.

Nocturnal Periodic Breathing during Acclimatization at Very High Altitude at Mount Muztagh Ata (7,546 m)

Quantitative data on ventilation during acclimatization at very high altitude are scant. Therefore, we monitored nocturnal ventilation and oxygen saturation in mountaineers ascending Mt. Muztagh Ata (7,546 m). To investigate whether periodic breathing persists during prolonged stay at very high altitude. A total of 34 mountaineers (median age, 46 yr; 7 women) climbed from 3,750 m within 19-20 days to the summit at 7,546 m. During ascent, repeated nocturnal recordings of calibrated respiratory inductive plethysmography, pulse oximetry, and scores of acute mountain sickness were obtained. Nocturnal oxygen saturation decreased, whereas minute ventilation and the number of periodic breathing cycles increased with increasing altitude. At the highest camp (6,850 m), median nocturnal oxygen saturation, minute ventilation, and the number of periodic breathing cycles were 64%, 11.3 L/min, and 132.3 cycles/h. Repeated recordings within 5-8 days at 4,497 m and 5,533 m, respectively, revealed increased oxygen saturation, but no decrease in periodic breathing. The number of periodic breathing cycles was positively correlated with days of acclimatization, even when controlled for altitude, oxygen saturation, and other potential confounders, whereas symptoms of acute mountain sickness had no independent effect on periodic breathing. Our field study provides novel data on nocturnal oxygen saturation, breathing patterns, and ventilation at very high altitude. It demonstrates that periodic breathing increases during acclimatization over 2 weeks at altitudes greater than 3,730 m, despite improved oxygen saturation consistent with a progressive increase in loop gain of the respiratory control system. Clinical trial registered with www.clinicaltrials.gov (NCT00514826).

Prediction and measurement of reverberation increase from electroacoustic architecture systems.

Electroacoustic architecture (EA) systems increase the reverberation time (RT) of rooms by regenerating the physical reverberation of the room, and/or adding electronic reverberation to the direct sound. In regenerative systems, the amount of regeneration is controlled by the loop gain of the system. Increasing loop gain is analogous to reducing the effective absorption in the room. The RT of the electronic reverberator is analogous to the decay time of a physically coupled room, and, therefore, analogous to adding cubic volume to the room. As the electronic RT is increased, there is a point above which the resulting reverberation will begin to be double sloped. This point depends on the gain. The higher the gain, the higher the electronic RT before the resulting reverberation double slopes. In previous work, the gain before feedback of EA systems has been predicted in a statistical approach based on the bulk properties of the room such as RT and cubic volume. This, in turn, can be used to predict the maximum possible power gain and RT increase before double sloping. In this paper, we measure systems in use in the field and compare the achieved performance with predictions.