Jerome Dempsey - US grants

It is our overall aim to determine the relative contributions of chemoreceptor vs. mechanical vs. metabolic vs. neurophysiologic "state"-related influences on the control of breathing in specific acute and chronic physiologic states in unanesthetized animals and humans. To this end, four areas of research are proposed, each devoted to a specific problem and one or more physiologic states. 1. What is the relative contribution of changes in cerebral fluid (H+) to eupnea in the presence of other chemoreceptor and non-chemoreceptor stimuli and inhibitors? Awake and anesthetized goat preparations will be used which permit differential effects to be imposed separately in the same animal on medullary chemoreception (via cerebral perfusion) and on carotid chemoreceptors (via isolated carotid perfusion). 2. How does physiologic sleep alter the effects of chemical and mechanical influences on the regulation of breathing--particularly the rhythmicity of breathing pattern? Unanesthetized humans and goats will be used to determine the relative roles of chemical stimuli and cerebral hypoxia in inducing periodic breathing and the effects of changes in pulmonary mechanics on inspiratory effort and respiratory muscle recruitment during sleep. 3. How do respiratory muscles adapt to heavy muscular exercise--mechanically and metabolically; and does the nature of this adaptation present a significant constraint to the accompanying ventilatory response? Exercise effects on pulmonary and chest wall mechanics and pressure development will be determined in healthy humans; and exercise effects on metabolism of the respiratory muscles will be assessed in rats. 4. How does the chronic ventilatory response to progesterone affect chest wall mechanics in patients with airway obstruction and chronic CO2 retention? Is the ventilatory response mediated (in guinea pigs and/or rats) by the action of specific metabolites of progesterone in neuroendocrine tissue?...and/or does progesterone exert effects on CNS serotonin metabolism which in turn effect ventilatory regulation? 5. What are the anatomical sites in the CNS and/or spinal cord of the serotonin-mediated nerve transmission involved in the regulation of breathing?

DESCRIPTION (Applicant's abstract): We will determine the contributions of the lung and the chest wall muscles to three key determinants of systemic oxygen transport during exercise, namely, cardiac output, locomotor muscle blood flow and arterial O2 content. First, we will test the hypothesis that the work of breathing (Wv) during exercise is an important determinant of the vascular resistance (VRL), blood flow (QL) and therefore the VO2 of the working limb locomotor muscles (VO2L) - especially at maximum exercise intensity in health and in patients with chronic heart failure. We will also determine the effects of exercise intensity, of hypoxia and of respiratory muscle training on the influence of Wv on QL. Microneurography will be used to assess if increased Wv affects limb muscle blood flow via reflexly triggered augmentation of muscle sympathetic nerve activity. A second aim concerned with cardiopulmonary interactions during exercise will address if respiratory-induced negative intrathoracic pressure during exercise compromises stroke volume and cardiac output in the healthy heart as well as the heart in failure. Thirdly, we will determine if the healthy female - of widely varying VO2max and age - has an increased susceptibility to exercise-induced diffusion limitation causing arterial hypoxemia (EIH), and also to expiratory flow limitation and to increased Wv. Our preliminary data support these proposals of a significant compromising effect of Wv on locomotor muscle blood flow at max exercise and of a strong influence of gender on exercise-induced arterial hypoxemia via diffusion limitation. Finally, we will quantify the relative contributions of Wv (via effects on QL) and diffusion limitation (via EIH) to the limitation of VO2max and exercise endurance performance with special emphasis on the highly fit, the female, healthy aging and the patient with chronic heart failure.

The research proposed in this SCOR application is aimed at the basic mechanisms, epidemiology, diagnosis and clinical consequences of sleep-disordered breathing (SDB). In healthy human subjects and in chronically instrumented unanesthetized animals, we will address three fundamental physiologic effects of sleep: a) the site and mechanism of action of hypocapnic-induced apnea; b) the contributions of fluctuating sleep state to breathing stability and upper airway dimensions; and c) the effects of sleep-induced changes in upper airway resistance on respiratory muscle recruitment. Four types of more narrowly focused longitudinal, clinically-oriented experiments address important issues related to SDB: a) humoral mechanisms of hypertension in the patient with SDB; b) cell biology of nocturnally-induced asthma; c) the effects of obesity and its reversal on the magnitude and site of sleep- induced airway obstruction; and d) application of the concept of the sleep-induced apneic threshold to patients with neuromuscular weakness and chronic lung disease as a means of intermittently "resting" respiratory muscles. Finally, our single largest undertaking brings an epidemiologic focus to the problem of cardiopulmonary disorders of sleep, predicated on the absolute necessity for longitudinal studies of a population-based sample in order to determine the natural history of these disorders. Our nested longitudinal study design, based on careful considerations of statistical power and advanced methods, will result in an ongoing elucidation of the natural history, risk factors and consequences of sleep disordered breathing. Critical to this study is the need for a comprehensive, sensitive, valid, quantitative test of the essential features of sleep disordered breathing, which is applicable to large numbers of subjects. We will design and validate such a test and use this broad and rigorously defined data base to determine the predictors of sleep disordered breathing and its clinical consequences in our population-based studies.

We propose further study of the regulation of breathing in various physiologic states in unanesthetized humans and dogs with specific emphasis on the underlying mechanisms and the mechanical consequences. To this end, the goals and procedures of this proposed research are as follows: 1. To determine the limits of the healthy pulmonary control system for gas transport, for respiratory muscle pressure development and for ventilatory output at extraordinarily elevated levels of metabolic demand. We hypothesize that limitations to function in the pulmonary control system will be manifested and will present significant limitations to maximum oxygen consumption, as the level of cardio-vascular and locomotor muscle fitness is increased in young (20-30 yrs) and elderly (55-75 yrs) highly endurance trained athletes, in the elite asthmatic athlete and in the racing greyhound. Special emphasis will be focused on alveolar to arterial gas exchange and on the mechanical constraints imposed by the chest wall on alveolar hyperventilation in heavy exercise. 2. To determine the effects of various types of acute and chronic ventilatory stimuli and inhibitors on respiratory muscle recruitment, on respiratory muscle length and on the timing of neuro-mechanical coupling throughout the breath. Physiologic states to be studied include acute and chronic chemoreceptor stimulation, locomotion and internal mechanical loading and unloading. These studies will also address the feed-forward and feed-back mechanisms responsible for these patterns of recruitment and the mechanical consequences of this recruitment to lung and chest wall function. 3. To quantitate the effects of sleep-induced increases in airway resistance on CO2 retention and respiratory muscle recruitment. Two closely related effects of sleep state will also be studied: a) the selective responses of inspiratory, expiratory abdominal and rib cage and upper airway "respiratory" muscles to inhibition secondary to small reductions in PaCO2 and to mechanical "unloading" in sleep; and b) the role of carotid chemoreceptors in the mediation of hypocapnic inhibition during all sleep stages.

The research proposed in this SCOR Renewal Proposal is aimed at the basic mechanisms, epidemiology and clinical consequences of sleep disordered breathing (SDB) and its treatment. 1. We will investigate the mechanisms by which the respiratory events which accompany SDB cause sustained hypertension. The hypothesis that an augmented carotid chemo-reflex sensitivity produces chronic elevations in sympathetic vaso motor outflow, and peripheral vascular resistance will be tested in humans and chronically-instrumented sleeping and anesthetized dogs. We will emphasize the role of "sensitization" of the carotid chemoreceptor in response to sustained, intermittent asphyxia as a major determinant of sustained hypertension. 2. We will determine - using the sleeping dog and human - those mechanisms which initiate and perpetuate sleep-induced instability of respiratory motor output and central apnea. We will also determine the influence of inhibition of respiratory motor output and central apnea on patency of the upper airway in human subjects who very widely in their susceptibility to upper airway obstruction. 3. We propose to continue to study the epidemiology of SDB with the aim of accumulating data from over night polysymography over a 5-9 year span in our cohort of 800 employed men and women with a wide range of SDB. These longitudinal data will permit us to address the pathophysiologic significance of mild, asymptomatic SDB and to investigate etiologic mechanisms. Based on our 4 years of cross-sectional data, we propose to use longitudinal studies to focus on specific questions of greatest relevance to public health, namely: the roles of aging and menopause in the development of SDB and the effect of SDB on hypersomnolence and systemic hypertension. 4. We will determine the cellular mechanisms responsible for nocturnal asthma. Our specific hypothesis focuses on the independent and interactive effects of sleep and circadian changes in cortisol and epinephrine on airway broncho-constriction and airway inflammation. 5. We will to develop computer-assisted methods for use in the efficient, accurate analysis of SDB. Specifically we will complete and extend our development of a Sleep Analysis Program for purposes of computer based quantitation of cardio-pulmonary events which occur in sleep and for the analysis of sleep state instability and continuity.

We will determine the mechanisms which cause breathing instability and central apnea during sleep and their effects on upper airway resistance, using chronically instrumented, unanesthetized dogs and human subjects. 1. How does central nervous system hypoxia affect the magnitude and stability of breathing pattern during wakefulness and sleep? We have developed a unique preparation for use in waking and sleeping dogs whereby the carotid chemoreceptor is perfused independently of the systemic and CNS circulations. 2. What mechanisms contribute to ventilatory instability and central apnea following perturbations in ventilatory output during sleep? We will examine the opposing effects of excitatory short-term potentiation vs the inhibitory effects of a) hypocapnia, b) vagal feedback from the lung and upper airway negative pressure and c) control system "inertia". 3. What is the role of carotid chemoreceptor hypocapnia, per se on respiratory motor output and timing? Using the isolated carotid chemoreceptor perfusion, we will test the role of steady-state and transient changes in hypocapnia on respiratory motor output in the awake and sleeping dog. 4. We will use passive and actively-induced hyperneas to determine the affect of transient changes in respiratory motor output and central apnea on upper airway patency and resistance in humans who represent a wide spectrum of susceptibility to airway closure. Sleep in humans is often characterized by marked and frequent fluctuations in ventilatory output and the drive to breathe, which has serious implications for sleep induced problems in gas exchange, sleep state stability and upper airway patency. We believe our proposed studies using commonly encountered perturbations in physiologic preparations provide a realistic and comprehensive approach to investigation of the complex mechanisms underlying sleep-disordered breathing and central apnea.

During sleep and with the loss of the "wakefulness" drive to pump and upper airway respiratory muscles, the control of breathing becomes highly dependent upon and vulnerable to reflexive feedback inputs from chemoreceptors and mechanoreceptors. Accordingly, sleep-induced breathing instabilities are common and have a significant prevalence even in the general population. Sleep unmasks a highly sensitive hypocapnic-induced apneic threshold, but we do not know what role this mechanism plays in various types of sleep-disordered breathing, because we do not know its sites of action, its changes in sensitivity in the presence of powerful background influences such as CNS hypoxia, chronic hypocapnia/hypercapnia, changing sleep states, or changing stimuli to breathe which might be specific to sleep. We will use sleeping humans and dogs, the latter with extra corporeal perfusion of isolated carotid chemoreceptors-to quantify the effect of these influences on both the apneic threshold and on the important stabilizing mechanism of short term potentiation of ventilatory output. This dog model with isolation of carotid chemoreceptors will also be used to address the question of central versus peripheral hypoxic effects on periodic breathing in sleep. A second dog model as well as human patients with chronic heart failure will be studied to address the mechanisms of Cheyne-Stokes respiration, with specific emphasis on the effects of the added stimulus to hyperventilation originating from the lungs of the patient in congestive heart failure. Finally, we will use dogs and humans-with and without innervated lungs-to address the role of non-chemical, mechanoreceptor inhibitory feedback effects during sleep on upper airway and pump muscles; a) influences from high frequency low amplitude pressure oscillations in the upper airway; b) the effects of amplitude, timing and duration of normocapnic mechanical ventilation on the resetting of inherent respiratory rhythm and on the "short-term inhibition" of respiratory motor output following cessation of phasic inhibitory sensory input. These latter studies conduced in sleep are important to testing the sensitivity of respiratory control mechanisms to mechanical feedback-a problem which remains relatively unexplored, especially in the human.

A large unique data-set has been obtained between 1988 and 1998 in a population of 1400 workers age 30 to 60 years, including an overnight sleep polysomnographic in-lab study conducted on two occasions over an eight year period. We wish to use the statistical power provided by computerized analysis of over 300,000 apneas and hypopneas in this non- clinical population. Our five specific aims are concerned with the causes, consequences and quantitation of sleep disordered breathing (SDB). 1. What are the physiologic characteristics of SDB events in the non-clinical population in terms of severity, high airway resistance, obstructive and central components and associated after- effects on EEG arousal and ventilatory overshoots? Do these important elements of the SDB event change as SDB progresses over time? Do the ventilatory or cardiovascular consequences of apnea or hypopnea and its immediate aftermath determine the likelihood of subsequent sleep- disordered breathing events? 2. What are the immediate and long-term cardiovascular consequences of sleep-disordered breathing events; what characteristics of these SDB events (such as O2 desaturation, arousal, ventilatory overshoot airway resistance, etc.) determine the cardiovascular responses and consequences? 3. What is the effect of aging on SDB and its sequelae as studied in the truly healthy elderly? 4. What role do anatomical characteristics of the upper airway play in determining the frequency and severity I and type of sleep-disordered breathing? Do these anatomical determinants differ in the general non- clinical population versus the obstructive sleep apnea (OSA) population? ... in the obese versus the non-obese? 5. To thoroughly evaluate our computerized analysis of SDB events in order to determine their accuracy and specificity for purposes of quantation and categorization of SDB events.

[unreadable] DESCRIPTION (provided by applicant): We propose three aims to explore respiratory influences on sympathetic vasoconstrictor activity, blood flow distribution and limb muscle fatigue during exercise in health and disease. AIM A: The COPD patient experiences flow limitation and increased elastic work of breathing during exercise, often accompanied by limb muscle fatigue and exercise intolerance. We will relieve much of the exercise-induced respiratory muscle work (using a proportional assist mechanical ventilator) or arterial hypoxemia in COPD patients and determine their influence on quadriceps fatigue and limb muscle blood flow and vascular conductance. This work is a clinical translation of our recent research in healthy subjects showing significant effects of reducing the work of breathing or preventing arterial O2 desaturation during high intensity exercise on limb muscle fatigue, blood flow and performance. AIM B: We will use multiple flow probes in a chronically instrumented canine, to determine how exercise influences the distribution of blood flow between inspiratory, expiratory and limb locomotor muscles. We will examine the influence of changes in respiratory muscle work, of activating the limb metaboreflex via vascular occlusion, and the relative effects of local adrenergic agonists and antagonists on vascular conductances in the limb vs. diaphragm vs. expiratory muscles during exercise. In light of the hyperventilation and heightened sympatho-excitation in the CHF patient during exercise, we will also determine how and why the available cardiac output is distributed between limb and respiratory muscles during exercise in the canine model with CHF (induced by cardiac pacing). AIM C: We will use healthy and CHF canine models to determine the contribution of the carotid chemoreceptors to sympathetic restraint of blood flow to the exercising limb muscles. Given our preliminary findings that carotid chemoreceptors account for about one-third of the total sympathetic constraint on limb vascular conductance during even mild intensity exercise in the healthy dog, we will use denervation of the sympathetic innervation of the chemoreceptors to determine if chemoreptor sensitivity is reset during exercise via sympathetically mediated vasoconstriction. In summary, our goal is to gain insight into the contributions of respiratory muscle work, arterial O2 content and the carotid chemoreceptors to the distribution of cardiac output during exercise in health, COPD and CHF and the resultant effects on muscle fatigue and performance. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (05) Comparative Effectiveness Research and specific Challenge Topic (05-HL-102) Treatment of Obstructive Sleep Apnea. About 15-30% of obstructive sleep apnea (OSA) patients have a poor tolerance for nasally-applied continuous positive airway pressure (CPAP) or develop problematic central apneas in response to this standard care. Although various alternative therapies have been tried, there is so far still no effective management for these refractory or difficult cases, probably because most available treatments are merely aimed at reducing the upper airway (UAW) collapsibility in unselected patients without concern for the dominant mechanism causing each individual's OSA. Recent research has revealed that breathing instability during sleep is more significant in those OSA patients who show high controller gain (ventilatory response to change of PaCO2) and/or high plant gain (eupnea PaCO2) of the respiratory control system, as manifested by a reduced CO2 reserve [?(eupneic PaCO2-apneic threshold PaCO2 )]. As we reported previously, periodic breathing and central apnea often lead to cyclical airway obstruction at the nadir of the respiratory drive in subjects with more collapsible upper airways. Accordingly, we hypothesize that correcting respiratory system instability will improve airway patency and breathing for those patients who are characterized by a significantly unstable respiratory motor output with mild to moderate levels of UAW collapsibility. This approach will be less effective with those who demonstrate less significant control instability and/or have extremely severe UAW collapsibility. We will characterize airway collapsibility and respiratory control system stability in 30 OSA patients. Then we will examine the effects on apnea/hypopnea index (AHI) and O2 desaturation of three different therapeutic strategies in these patients with a wide spectrum of breathing stability and UAW collapsibility:(1) prevention of transient hypocapnia via a unique iso-capnic rebreathing application;(2) reduction of plant gain via acetazolamide;and (3) a dampening of controller gain via hyperoxia, during sleep. We hypothesize that (1) Preventing transient hypocapnia should have the most significant effect of all three treatments on AHI in a broader range of OSA patients because it will prevent reductions in such a powerful determinant (i.e. PaCO2) of both upper airway and chest wall muscle recruitment as well as of respiratory system stability. Accordingly, we would expect this treatment to significantly reduce AHI even in patients with moderate airway collapsibility and with unstable ventilatory control. (2) Increasing respiratory motor output and reducing plant gain via carbonic anhydrase inhibition (and mild metabolic acidosis) will eliminate central apneas and significantly reduce obstructed and mixed apneas in subjects with a narrowed CO2 reserve due to increased plant or controller gain combined with mild levels of airway collapsibility, but may not be effective in those with severe UAW collapsibility or insignificant degrees of underlying breathing instability. (3) Hyperoxia will improve breathing stability and reduce OSA by reducing loop gain in OSA patients with a narrowed CO2 reserve (mainly due to increased controller gain) combined with mild levels of airway collapsibility, but may not be effective in those with severe UAW collapsibility or insignificant breathing instability. We anticipate that AHI in patients with even more severely unstable and collapsible UAW will not be improved by any of the three treatments because even a substantial amount of increased motor output to these dilator muscles during sleep will not be sufficient to open or prevent closure of such high collapsible airways. Arousal and wakefulness are likely required for airway patency in these patients. The proposed studies will deepen our understanding of the importance of heteropathy for each phenotype of OSA and will pave the way for individually targeted treatment approaches for managing refractory OSA. PUBLIC HEALTH RELEVANCE: We hope to improve the breathing during sleep in patients with OSA by individualizing their treatment to the patients'specific problem(s) associated with upper airway collapsibility and/or breathing stability.

Abstract Obstructive sleep apnea (OSA) needs to be treated with devices that will be utilized with greater compliance by patients than is currently the case with positive airway pressure. To this end, we recently showed that increased inspired CO2 via rebreathing was effective in reducing most obstructive and central apneas in OSA patients. Then, our UW team of bioengineers, physiologists, and sleep physicians built a novel variable dead space rebreathe device?with no added positive pressure?which monitors breath by breath ventilation and automatically adjusts the rebreathe dead space volume to add or subtract the level of inspired CO2 depending on the degree of sleep disordered breathing. This approach provides the minimum effective CO2 dose needed in individual OSA patients to stabilize central respiratory motor output and to recruit upper airway dilator muscles, thereby treating obstructive and central apneas. We propose to determine the effectiveness of this ?Smart CO2? treatment as well as its effects on sleep state stability, sleep quality, and blood pressure in 15 moderate to severe OSA patients studied over several nights. We expect the findings from the proposed study to be sufficient to determine if the ?Smart CO2? treatment is a viable approach to OSA treatment worthy of testing in a clinical trial.