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

Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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). Conclusions: 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

The Role of Phenotyping in the Personalised Management of OSA

Background: Obstructive sleep apnoea (OSA) is estimated to affect up to 1 billion people in the world. Those who fail first-line continuous positive airway pressure (CPAP) therapy have salvage treatment options available. Patient assessment can incorporate multidisciplinary teams to better select therapy. Traditional parameters that define OSA severity do not always correlate with symptoms of the disease. Newly identified pathophysiological “phenotypes” of airway vulnerability, low arousal threshold, loop gain and muscle responsiveness may explain the heterogeneity of OSA for up to two-thirds of patients. Little data exists on the effectiveness of phenotyping in a real-world clinical setting for patients undergoing contemporary management paradigms. Aims and Hypothesis: To evaluate the prevalence of the four OSA phenotypic traits and explore the clinical validity of endotyping in predicting future treatment outcomes. It is expected that non-responders to treatment will have unfavourable non-anatomical phenotypes. Design: An observational prospective cohort study of 49 patients referred after failure of CPAP for consideration of salvage therapy was conducted. Treatments included upper airway surgery (n = 17), mandibular advancement splint (n = 7), positional therapy (n = 7), weight loss (n = 4), nerve stimulation (n = 5) and combination therapy (n = 9). Treatment “success” was defined using polysomnographic parameters and patient-reported outcome measures of sleepiness and function. Phenotypic traits were analysed according to these outcomes. Results: Nearly all surgical patients had unfavourable loop gain (LG1 \u3e 0.72), which improved after surgical treatment (p \u3c .05). Patients who had decreased sleepiness (Epworth Sleepiness Scale reduction ≥ 3, total score \u3c 10, p = .01) after any treatment had favourable traits of low loop gain, lower arousal threshold and lower muscle compensation. There may be a potential role for phenotyping in predicting expected outcomes from salvage treatment for OSA, although more prospective clinical data is required to further investigate its utility and relevance

Central sleep apnea in patients with congestive heart failure

Central apnea during sleep represents a manifestation of breathing instability in many clinical conditions of varied etiologies. Central apnea is the result of transient cessation of ventilatory motor output, which represents that inhibitory influences favoring instability predominate over excitatory influence favoring stable breathing. This article will review the determinants of central apnea, the specific features of CHF-related central apnea, and outline a management approac

Contribution of the lung to the genesis of cheyne-stokes respiration in heart failure: Plant gain beyond chemoreflex gain and circulation time

Background-The contribution of the lung or the plant gain (PG; ie, change in blood gases per unit change in ventilation) to Cheyne-Stokes respiration (CSR) in heart failure has only been hypothesized by mathematical models, but never been directly evaluated.Methods and Results-Twenty patients with systolic heart failure (age, 72.4 +/- 6.4 years; left ventricular ejection fraction, 31.5 +/- 5.8%), 10 with relevant CSR (24-hour apnea-hypopnea index [AHI] &gt;= 10 events/h) and 10 without (AHI &lt;10 events/h) at 24-hour cardiorespiratory monitoring underwent evaluation of chemoreflex gain (CG) to hypoxia (CG(O2)) and hypercapnia (CG(CO2)) by rebreathing technique, lung-to-finger circulation time, and PG assessment through a visual system. PG test was feasible and reproducible (intraclass correlation coefficient, 0.98; 95% CI, 0.91-0.99); the best-fitting curve to express the PG was a hyperbola (R-2 &gt;= 0.98). Patients with CSR showed increased PG, CG(CO2) (but not CG(O2)), and lung-to-finger circulation time, compared with patients without CSR (all P&lt;0.05). PG was the only predictor of the daytime AHI (R=0.56, P=0.01) and together with the CG(CO2) also predicted the nighttime AHI (R=0.81, P=0.0003) and the 24-hour AHI (R=0.71, P=0.001). Lung-to-finger circulation time was the only predictor of CSR cycle length (R=0.82, P=0.00006).Conclusions-PG is a powerful contributor of CSR and should be evaluated together with the CG and circulation time to individualize treatments aimed at stabilizing breathing in heart failure

Breathing Re-Education and Phenotypes of Sleep Apnea: a Review

Four phenotypes of obstructive sleep apnea hypopnea syndrome (OSAHS) have been identified. Only one of these is anatomical. As such, anatomically based treatments for OSAHS may not fully resolve the condition. Equally, compliance and uptake of gold-standard treatments is inadequate. This has led to interest in novel therapies that provide the basis for personalized treatment protocols. This review examines each of the four phenotypes of OSAHS and explores how these could be targeted using breathing re-education from three dimensions of functional breathing: biochemical, biomechanical and resonant frequency. Breathing re-education and myofunctional therapy may be helpful for patients across all four phenotypes of OSAHS. More research is urgently needed to investigate the therapeutic benefits of restoring nasal breathing and functional breathing patterns across all three dimensions in order to provide a treatment approach that is tailored to the individual patient

Modeling Post Stroke Respiratory Dysfunction, Apneas and Cognitive Decline

Modeling Post Stroke Respiratory Dysfunction, Apneas and Cognitive Decline Anthony Patrizz, B.A. Advisory Professor: Louise McCullough M.D., Ph.D. Stroke is a major cause of mortality and the leading cause of long-term disability in the US. More than 60% of individuals suffering a first time stroke develop respiratory dysfunction, prolonging recovery and increasing mortality. Post-stroke cognitive decline is a major contributor to disability and nursing home placement, therefore the cognitive consequences of Stroke Induced Respiratory Dysfunction (SIRD) need to be explored if we hope to enhance functional recovery. The first step towards treatment of the negative consequences of SIRD is the development of appropriate animal models that will allow us to explore the pathophysiology of SIRD and provide the opportunity to test potential pharmacological agents. We developed and characterized an animal model of stroke induced respiratory dysfunction recapitulating the respiratory phenotype witnessed in the clinical population, characterized by incidences of apnea and hypoventilation. Interestingly, mice with high incidence of apneas display signs of progressive cognitive decline compared to those with low/no incidence of apneas. Histological analysis of vital brainstem respiratory control sites unveiled reactive astrocytosis, an important cell type in the neurovascular unit and an essential component of chemoreception. Respiratory dysfunction and brainstem astrocytosis was reproduced in mice that underwent intracerebroventricular injections of TGF-b. Suggesting the TGF-b signaling pathway contributes to the onset of astrogliosis and respiratory dysfunction. Our data suggests that stroke disrupts basal breathing rather than increasing chemoreceptor gain. Therefore, we predict treatments designed to stimulate breathing independent of chemoreceptor gain will improve respiratory instability, behavior, cognition and mortality. Systemic application of acetazolamide eliminated apneas while preventing further cognitive decline. This work not only developed a model of stroke induced respiratory dysfunction that recapitulates the respiratory phenotype witnessed in the clinical population, but also providing translational relevance to the field of stroke, aging, and cognitive decline. Successful treatment of SIRD may lead to significant improvements in post-stroke recovery and cognition

Unstable Ventilatory Control During Sleep After High Spinal Cord Injury: The Contribution Of Chemosensitivity And Hypoventilation

ABSTRACT UNSTABLE VENTILATORY CONTROL DURING SLEEP AFTER HIGH SPINAL CORD INJURY: THE CONTRIBUTION OF CHEMOSENSITIVITY AND HYPOVENTILATION by Amy T. Bascom May 2015 Advisor: Dr. Harry G. Goshgarian Major: Anatomy and Cell Biology Degree: Doctor of Philosophy A high prevalence of sleep-disordered breathing (SDB) after spinal cord injury (SCI) has been reported in the literature; however, the underlying mechanisms are not well understood. My studies had 2 aims: 1) to determine the effect of the withdrawal of the wakefulness drive to breathe on the degree of hypoventilation in SCI patients and able-bodied controls and 2) to determine the response of the peripheral chemoreceptors to brief hyperoxia (60 seconds of \u3e60% FiO2) and hypercapnia (a single breath of elevated CO2). I studied subjects with chronic cervical and high thoracic SCI and matched able-bodied subjects. For the first aim subjects underwent polysomnography, which included quantitative measurement of ventilation, timing, and upper airway resistance (RUA) on a breath-by-breath basis during transitions from wake to stage N1 sleep. Compared to able-bodied controls, SCI subjects had a significantly greater reduction in tidal volume during the transition from wake to N1sleep (from 0.51±0.21 L to 0.32±0.10 L vs. 0.47±0.13 L to 0.43±0.12 L; respectively, p\u3c0.05). Moreover, end-tidal CO2 and O2 were significantly altered from wake to sleep in SCI (38.9±2.7 vs. 40.6±3.4 mmHg; 94.1±7.1 vs. 91.2±8.3 mmHg; respectively, p˂0.05), but not in able-bodied controls (39.5±3.2 vs. 39.9±3.2 mmHg; 99.4±5.4 vs. 98.9±6.1 mmHg; respectively, p=ns). RUA was not significantly altered in either group. In aim 2 SCI subjects had a greater reduction in ventilation with hyperoxia administration (63.9±23.0 % of baseline VE) compared to able-bodied subjects (91.4±15.1 % of baseline VE, p\u3c0.05) and a higher ventilatory response to a single breath of CO2 (SCI: 0.78±0.4 L/min/mmHg vs. able-bodied: 0.26±0.1 L/min/mmHg, p\u3c0.05). In conclusion, individuals with SCI experience hypoventilation at sleep onset, which cannot be explained by upper airway mechanics and a high peripheral chemoreflex response to O2 and CO2. Sleep onset hypoventilation and high peripheral chemoresponsiveness may contribute to the development SDB in the SCI population

Effects on Breathing of Agonists to μ-opioid or GABA\u3csub\u3eA\u3c/sub\u3e Receptors Dialyzed into the Ventral Respiratory Column of Awake and Sleeping Goats

Pulmonary ventilation (V̇I) in awake and sleeping goats does not change when antagonists to several excitatory G protein-coupled receptors are dialyzed unilaterally into the ventral respiratory column (VRC). Concomitant changes in excitatory neuromodulators in the effluent mock cerebral spinal fluid (mCSF) suggest neuromodulatory compensation. Herein, we studied neuromodulatory compensation during dialysis of agonists to inhibitory G protein-coupled or ionotropic receptors into the VRC. Microtubules were implanted into the VRC of goats for dialysis of mCSF mixed with agonists to either μ-opioid (DAMGO) or GABAA (muscimol) receptors. We found: (1) V̇I decreased during unilateral but increased during bilateral dialysis of DAMGO, (2) dialyses of DAMGO destabilized breathing, (3) unilateral dialysis of muscimol increased V̇I, and (4) dialysis of DAMGO decreased GABA in the effluent mCSF. We conclude: (1) neuromodulatory compensation can occur during altered inhibitory neuromodulator receptor activity, and (2) the mechanism of compensation differs between G protein-coupled excitatory and inhibitory receptors and between G protein-coupled and inotropic inhibitory receptors

Clinical review: Long-term noninvasive ventilation

Noninvasive positive ventilation has undergone a remarkable evolution over the past decades and is assuming an important role in the management of both acute and chronic respiratory failure. Long-term ventilatory support should be considered a standard of care to treat selected patients following an intensive care unit (ICU) stay. In this setting, appropriate use of noninvasive ventilation can be expected to improve patient outcomes, reduce ICU admission, enhance patient comfort, and increase the efficiency of health care resource utilization. Current literature indicates that noninvasive ventilation improves and stabilizes the clinical course of many patients with chronic ventilatory failure. Noninvasive ventilation also permits long-term mechanical ventilation to be an acceptable option for patients who otherwise would not have been treated if tracheostomy were the only alternative. Nevertheless, these results appear to be better in patients with neuromuscular/-parietal disorders than in chronic obstructive pulmonary disease. This clinical review will address the use of noninvasive ventilation (not including continuous positive airway pressure) mainly in diseases responsible for chronic hypoventilation (that is, restrictive disorders, including neuromuscular disease and lung disease) and incidentally in others such as obstructive sleep apnea or problems of central drive

Sleep and Breathing at High Altitude

This thesis describes the work carried out during four treks, each over 10-11 days, from 1400m to 5000m in the Nepal Himalaya and further work performed during several two-night sojourns at the Barcroft Laboratory at 3800m on White Mountain in California, USA. Nineteen volunteers were studied during the treks in Nepal and seven volunteers were studied at White Mountain. All subjects were normal, healthy individuals who had not travelled to altitudes higher than 1000m in the previous twelve months. The aims of this research were to examine the effects on sleep, and the ventilatory patterns during sleep, of incremental increases in altitude by employing portable polysomnography to measure and record physiological signals. A further aim of this research was to examine the relationship between the ventilatory responses to hypoxia and hypercapnia, measured at sea level, and the development of periodic breathing during sleep at high altitude. In the final part of this thesis the possibility of preventing and treating Acute Mountain Sickness with non-invasive positive pressure ventilation while sleeping at high altitude was tested. Chapter 1 describes the background information on sleep, and breathing during sleep, at high altitudes. Most of these studies were performed in hypobaric chambers to simulate various high altitudes. One study measured sleep at high altitude after trekking, but there are no studies which systematically measure sleep and breathing throughout the whole trek. Breathing during sleep at high altitude and the physiological elements of the control of breathing (under normal/sea level conditions and under the hypobaric, hypoxic conditions present at high altitude) are described in this Chapter. The occurrence of Acute Mountain Sickness (AMS) in subjects who travel form near sea level to altitudes above 3000m is common but its pathophysiology not well understood. The background research into AMS and its treatment and prevention are also covered in Chapter 1. Chapter 2 describes the equipment and methods used in this research, including the polysomnographic equipment used to record sleep and breathing at sea level and the high altitude locations, the portable blood gas analyser used in Nepal and the equipment and methodology used to measure each individual’s ventilatory response to hypoxia and hypercapnia at sea level before ascent to the high altitude locations. Chapter 3 reports the findings on the changes to sleep at high altitude, with particular focus on changes in the amounts of total sleep, the duration of each sleep stage and its percentage of total sleep, and the number and causes of arousals from sleep that occurred during sleep at increasing altitudes. The lightest stage of sleep, Stage 1 non-rapid eye movement (NREM) sleep, was increased, as expected with increases in altitude, while the deeper stages of sleep (Stages 3 and 4 NREM sleep, also called slow wave sleep), were decreased. The increase in Stage 1 NREM in this research is in agreement with all previous findings. However, slow wave sleep, although decreased, was present in most of our subjects at all altitudes in Nepal; this finding is in contrast to most previous work, which has found a very marked reduction, even absence, of slow wave sleep at high altitude. Surprisingly, unlike experimental animal studies of chronic hypoxia, REM sleep was well maintained at all altitudes. Stage 2 NREM and REM sleep, total sleep time, sleep efficiency and spontaneous arousals were maintained at near sea level values. The total arousal index was increased with increasing altitude and this was due to the increasing severity of periodic breathing as altitude increased. An interesting finding of this research was that fewer than half the periodic breathing apneas and hypopneas resulted in arousal from sleep. There was a minor degree of upper airway obstruction in some subjects at sea level but this was almost resolved by 3500m. Chapter 4 reports the findings on the effects on breathing during sleep of the progressive increase of altitude, in particular the occurrence of periodic breathing. This Chapter also reports the results of changes to arterial blood gases as subjects ascended to higher altitudes. As expected, arterial blood gases were markedly altered at even the lowest altitude in Nepal (1400m) and this change became more pronounced at each new, higher altitude. Most subjects developed periodic breathing at high altitude but there was a wide variability between subjects as well as variability in the degree of periodic breathing that individual subjects developed at different altitudes. Some subjects developed periodic breathing at even the lowest altitude and this increased with increasing altitude; other subjects developed periodic breathing at one or two altitudes, while four subjects did not develop periodic breathing at any altitude. Ventilatory responses to hypoxia and hypercapnia, measured at sea level before departure to high altitude, was not significantly related to the development of periodic breathing when the group was analysed as a whole. However, when the subjects were grouped according to the steepness of their ventilatory response slopes, there was a pattern of higher amounts of periodic breathing in subjects with steeper ventilatory responses. Chapter 5 reports the findings of an experimental study carried out in the University of California, San Diego, Barcroft Laboratory on White Mountain in California. Seven subjects drove from sea level to 3800m in one day and stayed at this altitude for two nights. On one of the nights the subjects slept using a non-invasive positive pressure device via a face mask and this was found to significantly improve the sleeping oxyhemoglobin saturation. The use of the device was also found to eliminate the symptoms of Acute Mountain Sickness, as measured by the Lake Louise scoring system. This finding appears to confirm the hypothesis that lower oxygen saturation, particularly during sleep, is strongly correlated to the development of Acute Mountain Sickness and may represent a new treatment and prevention strategy for this very common high altitude disorder