Ventilatory Control System Research Articles

Inaugural Review Prize 2023: The exercise hyperpnoea dilemma: A 21st-century perspective.

During mild or moderate exercise, alveolar ventilation increases in direct proportion to metabolic rate, regulating arterial CO2 pressure near resting levels. Mechanisms giving rise to the hyperpnoea of exercise are unsettled despite over a century of investigation. In the past three decades, neuroscience has advanced tremendously, raising optimism that the 'exercise hyperpnoea dilemma' can finally be solved. In this review, new perspectives are offered in the hope of stimulating original ideas based on modern neuroscience methods and current understanding. We first describe the ventilatory control system and the challenge exercise places upon blood-gas regulation. We highlight relevant system properties, including feedforward, feedback and adaptive (i.e., plasticity) control of breathing. We then elaborate a seldom explored hypothesis that the exercise ventilatory response continuously adapts (learns and relearns) throughout life and ponder if the memory 'engram' encoding the feedforward exercise ventilatory stimulus could reside within the cerebellum. Our hypotheses are based on accumulating evidence supporting the cerebellum's role in motor learning and the numerous direct and indirect projections from deep cerebellar nuclei to brainstem respiratory neurons. We propose that cerebellar learning may be obligatory for the accurate and adjustable exercise hyperpnoea capable of tracking changes in life conditions/experiences, and that learning arises from specific cerebellar microcircuits that can be interrogated using powerful techniques such as optogenetics and chemogenetics. Although this review is speculative, we consider it essential to reframe our perspective if we are to solve the till-now intractable exercise hyperpnoea dilemma.

Automatic Measurement of Loop Gain Based on Pseudorandom Binary Sequence CO2 Stimulation.

Measurement of loop gain in patients with obstructive sleep apnea (OSA) is of great importance for determining the cause of OSA and realizing precision medicine. In this study, automatic measurement of loop gain is carried out during wakefulness based on the pseudorandom binary sequence (PRBS) CO2 stimulation method. A respiratory data acquisition platform is designed and constructed to automate the processes of gas configuration, ventilatory stimulation with CO2 and data acquisition. The respiratory data are substituted into the model of the ventilatory control system for parameter identification, and the loop gain values are calculated and then compared with the apnea-hypopnea index (AHI) measured in a hypoxia chamber. A positive correlation is found between loop gain and AHI measured in the hypoxia chamber, with the linear correlation coefficient of approximately 0.65. The feasibility of automatic measurement of loop gain using the respiratory data acquisition platform based on the PRBS CO2 stimulation method is validated, and the measured loop gain values can be used to assess the stability of ventilatory control. This study provides an automated, rapid, and instrumented solution for loop gain measurement, laying the foundation for wide-scale clinical application of the PRBS CO2 stimulation method.

Anatomical Basis of Obstructive Sleep Apnoea: A Review of Randomized Controlled Trials.

Repeated obstruction and closure of the upper airway, sporadic hypoxic episodes, and sympathetic activity are symptoms of obstructive sleep apnea (OSA). Obstructive sleep apnoea is due to a combination of altered upper airway structure and muscular function, a low arousal threshold and increased loop gain.Although recurrent upper airway (UA) collapse during sleep is the most frequent clinical hallmark of OSA, the exact cause of this collapse is unknown. Furthermore, while continuous positive airway pressure aids in the management of OSA, many patients find it intolerable. As a result, a better knowledge of the causes of OSA may result in more effective treatments. We did a review of randomized controlled trials that were done in this regard in the last 10 years and whose full-text version is available on the PubMed database. A total of 20 articles were finalized for review after applying our criteria. The articles have proposed different theories regarding the anatomical basis responsible for obstructive sleep apnoea. The theories proposed by different studies in the last decade include reduced genioglossus and hypoglossal nerve activity, the pharyngeal muscles' failure to keep the airway open or tighten it, tonsils and adenoid hypertrophy, an oversensitive ventilatory control system and low respiratory arousal threshold, mandibular position, pharyngeal muscles' high sympathetic drive, cephalometric alterations such as mandibular and hyoid bone position and the length of the soft palate, obesity, and neck fat and fluid re-distribution in the body, from the lower to the upper parts while reclining. Given the diverse etiological characteristics of OSA patients and to increase our knowledge of the condition, additional study into this group is required. Filling any knowledge gaps that may exist in the anatomical basis of the onset of OSA is the main objective of this review paper.

Respiratory considerations in patients with neuromuscular disorders.

Patients with neuromuscular disorders (NMDs) develop respiratory impairment as muscles weaken. Ensuing complications include reductions in lung volume, compliance, and cough ability and increased risk for lung infections. Sleep disordered breathing results from weakened upper airway muscles and/or impaired central ventilatory control systems. Evaluation includes measurement of seated and supine vital capacity (VC) and respiratory muscle strength. Assisted cough techniques facilitate airway clearance. The decision to initiate assisted ventilation is multifactorial, and may include consideration of patient symptoms, spirometry, pulmonary pressures, sleep studies or blood gas values. Most patients prefer noninvasive ventilation to enhance mobility and independence. Tracheostomy is indicated when bulbar function is impaired and cough assist measures fail to clear the airway. Technological advances in respiratory support have improved quality of life and longevity. Home care is the best option for most patients but remains a challenge, especially for caregivers with regard to physical, emotional, and financial implications, as well as social, administrative, and insurance concerns.

Control of Breathing in Ectothermic Vertebrates.

The ectothermic vertebrates are a diverse group that includes the Fishes (Agnatha, Chondrichthyes, and Osteichthyes), and the stem Tetrapods (Amphibians and Reptiles). From an evolutionary perspective, it is within this group that we see the origin of air-breathing and the transition from the use of water to air as a respiratory medium. This is accompanied by a switch from gills to lungs as the major respiratory organ and from oxygen to carbon dioxide as the primary respiratory stimulant. This transition first required the evolution of bimodal breathing (gas exchange with both water and air), the differential regulation of O2 and CO2 at multiple sites, periodic or intermittent ventilation, and unsteady states with wide oscillations in arterial blood gases. It also required changes in respiratory pump muscles (from buccopharyngeal muscles innervated by cranial nerves to axial muscles innervated by spinal nerves). The question of the extent to which common mechanisms of respiratory control accompany this progression is an intriguing one. While the ventilatory control systems seen in all extant vertebrates have been derived from common ancestors, the trends seen in respiratory control in the living members of each vertebrate class reflect both shared-derived features (ancestral traits) as well as unique specializations. In this overview article, we provide a comprehensive survey of the diversity that is seen in the afferent inputs (chemo and mechanoreceptor), the central respiratory rhythm generators, and the efferent outputs (drive to the respiratory pumps and valves) in this group. © 2022 American Physiological Society. Compr Physiol 12: 1-120, 2022.

Ventilatory control instability as a predictor of persistent periodic breathing in preterm infants.

BackgroundPeriodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally.MethodsInfants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32–36 weeks postmenstrual age (PMA) (N = 32), 36–40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs.ResultsThe time spent in PB decreased from 32–36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean ± SEM: 0.445 ± 0.01 vs 0.388 ± 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32–36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA.ConclusionsThe course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32–36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA.Impact The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear.Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age.Infants who display greater ventilatory control instability at 32–36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age.Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects.

Obstructive sleep apnea and respiratory center regulation abnormality.

Obstructive sleep apnea (OSA) is a complex disease in which phenotypic analysis and understanding pathological mechanisms facilitate personalized treatment and outcomes. However, the pathophysiology responsible for this robust observation is incompletely understood. The objective of the present work was to review how respiratory center regulation varies during sleep and wakeness in patients with OSA. We searched for relevant articles up to December 31, 2019 in PubMed database. This review examines the current literature on the characteristics of respiratory center regulation during wakefulness and sleep in OSA, detection method, and phenotypic treatment for respiratory center regulation. Mechanisms for ventilatory control system instability leading to OSA include different sleep stages in chemoresponsiveness to hypoxia and hypercapnia and different chemosensitivity at different time. One can potentially stabilize the breathing center in sleep-related breathing disorders by identifying one or more of these pathophysiological mechanisms. Advancing mechanism research in OSA will guide symptom research and provide alternate and novel opportunities for effective treatment for patients with OSA.

Is the healthy respiratory system built just right, overbuilt, or underbuilt to meet the demands imposed by exercise?

In the healthy, untrained young adult, a case is made for a respiratory system (airways, pulmonary vasculature, lung parenchyma, respiratory muscles, and neural ventilatory control system) that is near ideally designed to ensure a highly efficient, homeostatic response to exercise of varying intensities and durations. Our aim was then to consider circumstances in which the intra/extrathoracic airways, pulmonary vasculature, respiratory muscles, and/or blood-gas distribution are underbuilt or inadequately regulated relative to the demands imposed by the cardiovascular system. In these instances, the respiratory system presents a significant limitation to O2 transport and contributes to the occurrence of locomotor muscle fatigue, inhibition of central locomotor output, and exercise performance. Most prominent in these examples of an "underbuilt" respiratory system are highly trained endurance athletes, with additional influences of sex, aging, hypoxic environments, and the highly inbred equine. We summarize by evaluating the relative influences of these respiratory system limitations on exercise performance and their impact on pathophysiology and provide recommendations for future investigation.

Obstructive sleep apnea and pulmonary hypertension: a bidirectional relationship.

Citation:Mesarwi O, Malhotra A. Obstructive sleep apnea and pulmonary hypertension: a bidirectional relationship. J Clin Sleep Med. 2020;16(8):1223–1224.

Association of Rapid Eye Movement Sleep (REM) Dominant Obstructive Sleep Apnea (OSA)(REM-OSA) Versus Non-REM Sleep Dominant OSA (non-REM OSA) and Suicidal Ideation in Posttraumatic Stress Disorder (PTSD)

Obstructive sleep apnea (OSA) severity in PTSD correlates directly to suicidal ideation (SI), with depression as a mediator. OSA severity varies with sleep stages as the ventilatory control system sensitivity (loop gain) is significantly lower (and ventilatory control more stable) during REM versus non-REM sleep. This study examined the association of OSA and SI in PTSD patients with REM-sleep dominant OSA (REM-OSA) versus non-REM sleep dominant OSA (non-REM OSA).

Mitigation of Exercise Oscillatory Ventilation Score by Cardiac Resynchronization Therapy

BackgroundExercise oscillatory ventilation (EOV) is a consequence of ventilatory control system instability and is commonly observed in patients with advanced heart failure (HF); it is associated with adverse prognosis. The goal of this study was to evaluate the effects of cardiac resynchronization therapy (CRT) on oscillatory ventilation as quantified by a proposed EOV score. Methods and ResultsConsecutive patients with HF (N = 35) who underwent clinically indicated CRT, cardiopulmonary exercise testing and carbon dioxide (CO2) chemosensitivity by rebreathe before and 4–6 months after CRT were included in this post hoc analysis. With CRT, EOV scores improved in 22 patients (63%). In these patients, left ventricular ejection fraction, left atrial volume, brain natriuretic peptide concentration, and CO2 chemosensitivity significantly improved after CRT (P < 0.05). Furthermore, minute ventilation per unit CO2 production significantly decreased, and end-tidal CO2 increased at rest and at peak exercise post-CRT. Multiple regression analysis showed only the change of CO2 chemosensitivity to be significantly associated with the improvement of the EOV score (b = 0.64; F = 11.3; P = 0.004). In the group without EOV score improvement (n = 13), though left ventricular ejection fraction significantly increased with CRT (P = 0.015), no significant changes in ventilation or gas exchange were observed. ConclusionThe EOV score was mitigated by CRT and was associated with decreased CO2 chemosensitivity.

Neonatal Intermittent Hypoxia Induces Lasting Sex-Specific Augmentation of Rat Microglial Cytokine Expression.

Sleep disordered breathing (SDB) affects 3–5% of the pediatric population, including neonates who are highly susceptible due to an underdeveloped ventilatory control system, and REM-dominated sleep. Although pediatric SDB is associated with poor cognitive outcomes, very little research has focused on models of pediatric SDB, particularly in neonates. In adults and neonates, intermittent hypoxia (IH), a hallmark of SDB, recapitulates multiple physiological aspects of severe SDB, including neuronal apoptosis, sex-specific cognitive deficits, and neuroinflammation. Microglia, resident CNS immune cells, are important mediators of neurodevelopment and neuroinflammation, but to date, no studies have examined the molecular properties of microglia in the context of neonatal IH. Here, we tested the hypothesis that neonatal IH will enhance microglial inflammation and sex-specifically lead to long-term changes in working memory. To test this hypothesis, we exposed post-natal day (P1) neonates with dams to an established adult model of pathological IH consisting of 2 min cycles of 10.5% O2 followed by 21% O2, 8 h/day for 8 days. We then challenged the offspring with bacterial lipopolysaccharide (LPS) at P9 or at 6–8 weeks of age and immunomagnetically isolated microglia for gene expression analyses and RNA-sequencing. We also characterized neonatal CNS myeloid cell populations by flow cytometry analyses. Lastly, we examined working memory performance using a Y-maze in the young adults. Contrary to our hypothesis, we found that neonatal IH acutely augmented basal levels of microglial anti-inflammatory cytokines, attenuated microglial responses to LPS, and sex-specifically altered CNS myeloid populations. We identified multiple sex differences in basal neonatal microglial expression of genes related to chemotaxis, cognition, and aging. Lastly, we found that basal, but not LPS-induced, anti-inflammatory cytokines were augmented sex-specifically in the young adults, and that there was a significant interaction between sex and IH on basal working memory. Our results support the idea that neonates may be able to adapt to IH exposures that are pathological in adults. Further, they suggest that male and female microglial responses to IH are sex-specific, and that these sex differences in basal microglial gene expression may contribute to sexual dimorphisms in vulnerability to IH-induced cognitive disruption.

Acute and chronic changes in the control of breathing in a hyperoxia‐induced model of bronchopulmonary dysplasia

Infants born very prematurely (&lt;28 weeks gestation) have immature lungs and often require supplemental oxygen. However, long‐term hyperoxia exposure can arrest lung development leading to bronchopulmonary dysplasia (BPD), which increases acute and long‐term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we tested the hypothesis that there would be age‐dependent adaptations in the control of breathing in an established rat model of hyperoxia‐induced BPD. Hyperoxia exposure (FIO2: 0.9 from 0–10 days of life) led to a BPD‐like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (VE) and age‐dependent changes in breath‐to‐breath tidal volume and breathing frequency variability. Hyperoxia‐exposed rats had normal hypoxic ventilatory responses, oxygen saturation (SpO2) in room air, but greater reductions in SpO2 during acute hypoxia (12% O2) indicating reduced hypoxic sensitivity and/or hypoventilation due to diseased lungs. However, VE was increased indicating an increase in respiratory drive. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within 6 of 8 and 1 of 8 key brainstem regions controlling breathing, respectively, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD‐like phenotype and age‐dependent adaptations in VE that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.Support or Funding InformationChildren's Research Hospital of Wisconsin Research Institute, NIH R01 HL 122358, &amp; Parker B. Francis FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute and chronic changes in the control of breathing in a rat model of bronchopulmonary dysplasia.

Infants born very prematurely (<28 wk gestation) have immature lungs and often require supplemental oxygen. However, long-term hyperoxia exposure can arrest lung development, leading to bronchopulmonary dysplasia (BPD), which increases acute and long-term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we assessed potential age-dependent adaptations in the control of breathing in an established rat model of BPD associated with hyperoxia. Hyperoxia exposure ( ; 0.9 from 0 to 10 days of life) led to a BPD-like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (V̇e) and age-dependent changes in breath-to-breath variability. Hyperoxia-exposed rats had normal oxygen saturation ( ) in room air but greater reductions in during acute hypoxia (12% O2) that were likely due to lung injury. Moreover, acute ventilatory sensitivity was reduced at P12 to P14. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within six of eight or one of eight key brainstem regions, respectively, controlling breathing, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD-like phenotype and age-dependent adaptations in V̇e that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.

Bilateral carotid sinus nerve transection exacerbates morphine-induced respiratory depression

Opioid-induced respiratory depression (OIRD) involves decreased sensitivity of ventilatory control systems to decreased blood levels of oxygen (hypoxia) and elevated levels of carbon dioxide (hypercapnia). Understanding the sites and mechanisms by which opioids elicit respiratory depression is pivotal for finding novel therapeutics to prevent and/or reverse OIRD. To examine the contribution of carotid body chemoreceptors OIRD, we used whole-body plethysmography to evaluate hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses including changes in frequency of breathing, tidal volume, minute ventilation and inspiratory drive, after intravenous injection of morphine (10 mg/kg) in sham-operated (SHAM) and in bilateral carotid sinus nerve transected (CSNX) Sprague-Dawley rats. In SHAM rats, morphine produced sustained respiratory depression (e.g., decreases in tidal volume, minute ventilation and inspiratory drive) and reduced the HVR and HCVR responses. Unexpectedly, morphine-induced suppression of HVR and HCVR were substantially greater in CSNX rats than in SHAM rats. This suggests that morphine did not compromise the function of the carotid body-chemoafferent complex and indeed, that the carotid body acts to defend against morphine-induced respiratory depression. These data are the first in vivo evidence that carotid body chemoreceptor afferents defend against rather than participate in OIRD in conscious rats. As such, drugs that stimulate ventilation by targeting primary glomus cells and/or chemoafferent terminals in the carotid bodies may help to alleviate OIRD.

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.

Averting Opioid-induced Respiratory Depression without Affecting Analgesia.

The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

Ventilatory control sensitivity in patients with obstructive sleep apnea is sleep stage dependent.

The severity of obstructive sleep apnea (OSA) is known to vary according to sleep stage; however, the pathophysiology responsible for this robust observation is incompletely understood. The objective of the present work was to examine how ventilatory control system sensitivity (i.e. loop gain) varies during sleep in patients with OSA. Loop gain was estimated using signals collected from standard diagnostic polysomnographic recordings performed in 44 patients with OSA. Loop gain measurements associated with nonrapid eye movement (NREM) stage 2 (N2), stage 3 (N3), and REM sleep were calculated and compared. The sleep period was also split into three equal duration tertiles to investigate how loop gain changes over the course of sleep. Loop gain was significantly lower (i.e. ventilatory control more stable) in REM (Mean ± SEM: 0.51 ± 0.04) compared with N2 sleep (0.63 ± 0.04; p = 0.001). Differences in loop gain between REM and N3 (p = 0.095), and N2 and N3 (p = 0.247) sleep were not significant. Furthermore, N2 loop gain was significantly lower in the first third (0.57 ± 0.03) of the sleep period compared with later second (0.64 ± 0.03, p = 0.012) and third (0.64 ± 0.03, p = 0.015) tertiles. REM loop gain also tended to increase across the night; however, this trend was not statistically significant [F(2, 12) = 3.49, p = 0.09]. These data suggest that loop gain varies between REM and NREM sleep and modestly increases over the course of sleep. Lower loop gain in REM is unlikely to contribute to the worsened OSA severity typically observed in REM sleep, but may explain the reduced propensity for central sleep apnea in this sleep stage.

0895 THE EFFECT OF LOOP GAIN ON EFFICACY OF SUPPLEMENTAL OXYGEN FOR TREATMENT OF INFANTS WITH OBSTRUCTIVE SLEEP APNEA (OSA)

Recent work from our group has demonstrated that the use of supplemental oxygen (suppO2) in infants with OSA results in fewer respiratory events and improved oxygenation without adversely affecting alveolar ventilation. However, a common observation in our study was that suppO2 was effective in some, but not all, infants. Based on data for adult patients with OSA, the administration of suppO2 seems most effective in those with a hypersensitive ventilatory control system (i.e. high loop gain). Accordingly, we hypothesized that infants who respond well to suppO2 have a higher measured loop gain than those who respond poorly. We conducted a retrospective analysis of 10 infants with OSA treated with suppO2 from 2007–2013. Subjects underwent a room air, diagnostic sleep study (RA-PSG) followed by a study for suppO2 titration (O2-PSG) on a separate night. The five subjects who best responded to suppO2, defined as those that showed the largest percent reduction in obstructive apnea hypopnea index (O-AHI) and those five with the worst response to suppO2 were identified. Loop gain was estimated from spontaneous breathing using 3 minute windows of sleep containing at least one respiratory event. Square root transformed nasal pressure airflow was used to provide a surrogate of ventilation. A standard model of ventilatory control (gain, time-constant, delay) that best matched ventilation data during periods of unobstructed breathing was used to estimate loop gain at the natural ‘resonant’ frequency (LGn) by a scorer blinded to responder condition. SuppO2 significantly reduced the O-AHI in responders (22.2 ± 10.0 events.hr-1 vs. 2.1 ± 1.0 events.hr-1: p<0.05) whereas it remained unchanged in the non-responders (18.3 ± 14.1 events.hr-1 vs. 20.3 ± 18.1 events.hr-1: p=NS). Compared to non-responders, responders displayed an elevated LGn (0.48 ± 0.07 vs. 0.36 ± 0.06: p<0.05). Our preliminary evidence suggests that infants with OSA who respond to suppO2 therapy have a higher loop gain compared to non-responders. These data suggest that similar to adults with OSA, ventilatory instability is an important mechanism causing OSA in some infants.

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.