Respiratory Physiology During Sleep Vipin Malik, MD*, Daniel Smith, MD, Teofilo Lee-Chiong Jr, MD KEYWORDS Ventilatory regulation Respiratory motoneurons Hypoxemia Hypercapnia Pneumotaxic center Apneustic center Chemoreceptors KEY POINTS Ventilatory regulation is conceptually best understood as a 3-part system consisting of a central controller, sensors, and effectors. The effectors of respiration include the respiratory motoneurons and muscles, which are involved in inspiration and expiration. Positional changes during sleep (ie, nonupright position) affect the mechanics of breathing significantly. Both hypoxemia and hypercapnia can develop during sleep in patients with chronic obstructive pulmonary disease. Upper-airway narrowing and excess weight, if present, can increase the mechanical load on the respiratory system as well as breathing work. The respiratory system provides continuous CONTROL OF RESPIRATION homeostasis of partial pressures of arterial oxygen Ventilatory regulation is conceptually best under- (PaO ), carbon dioxide (PCO ), and pH levels during 2 2 stood as a 3-part system consisting of a central constantly changing physiologic conditions. This controller, sensors, and effectors. Sensors primarily elegant system responds promptly to subtle varia- include central and peripheral chemoreceptors, tions in metabolism occurring in both health and vagal pulmonary sensors, and chest-wall and respi- disease. During wakefulness, volitional influences ratory muscle afferents. Data from these sensors can override this automatic control. Modifications regarding dynamic oxygen and CO levels, lung occur in the regulation and control of respiration 2 volumes, and respiratory muscle activity are contin- with the onset of sleep. Furthermore, these uously transmitted to the central controller. Within changes differ significantly with specific sleep the medulla, the central controller generates an auto- stages. These alterations in respiratory control mated rhythm of respiration that is constantly modi- can result in the pathogenesis of sleep-related fied in response to an integrated input from the breathing disorders and limit the usual respiratory various receptors. The controller modulates motor compensatory changes to specific disease states. output from the brainstem to influence the activity This article reviews the normal physiology of respi- of the effectors, namely respiratory motoneurons ration in both awake and sleep states, and and muscles. These effectors then alter minute discusses the effects of common disease ventilation and gas exchange accordingly (Table 1). processes and medications on the respiratory The medullary ventilatory center consists of physiology of sleep. neurons in the dorsal respiratory group (DRG) A version of this article originally appeared in Sleep Medicine Clinics Volume 5, Issue 2. Section of Sleep Medicine, National Jewish Medical and Research Center, Denver, CO, USA * Corresponding author. Section of Sleep Medicine, Division of Critical Care and Hospital Medicine, National Jewish Health, 1400 Jackson Street, M323, Denver, CO 80206. E-mail address: [email protected] Sleep Med Clin 7 (2012) 497–505 http://dx.doi.org/10.1016/j.jsmc.2012.06.011 1556-407X/12/$ – see front matter Ó 2012 Published by Elsevier Inc. sleep.theclinics.com 498 Malik et al Table 1 Control of respiration Controllers/Effectors Location Afferents Effects Dorsal Respiratory group Dorsomedial medulla, ventrolateral to Upper airways, intra-arterial Increased frequency of a ramping the solitary tract chemoreceptors, and lung afferents pattern of firing during continued via the 5th,9th and 10th cranial nerves, inspiration respectively Ventral Respiratory Group Ventrolateral medulla Response to the need for forced Respiratory effectors muscles are expiration occurring during exercise innervated from the VRG via phrenic, or with increased airways resistance intercostal and abdominal motoneurons. Pneumotaxic center Rostral pons consists of the nucleus Pontine input serves to fine tune Duration of inspiration and provide parabrachialis and the Kolliker-Fuse respiratory patterns and may tonic input to respiratory pattern nucleus. additionally modulate responses to generator hypercapnia, hypoxia, and lung inflation Apneustic center Lower pons Pneumotaxic center and vagal input Provide signals that smoothly terminate inspiratory efforts Central Chemoreceptors Ventrolateral surface of medulla Extracellular fluid [H+] concentration Respond to changes in brain extracellular fluid [H+] concentration Peripheral Chemoreceptors Carotid bodies and the aortic bodies Afferent input to the medulla through Respond mainly to PaO2, but also to th the 9 cranial nerve changes in PaCO2 and pH Pulmonary Mechanoreceptors 1. PSRs are located in proximal airway 1. Respond to inflation, especially in the smooth muscles. setting of hyperinflation 2. J-receptors are located in the 2. Mediate dyspnea in the setting of juxtacapillary area and appear to pulmonary vascular congestion mediate dyspnea in the setting of 3. Affect bronchomotor tone and pulmonary vascular congestion respond to pulmonary inflammation 3. Bronchial c-fibers Q1 Respiratory Physiology During Sleep 499 and the ventral respiratory group (VRG) (Fig. 1).1 appears to be active primarily during inspiration, Located in the dorsomedial medulla, ventrolateral with increased frequency of a ramping pattern of to the solitary tract, the DRG was previously firing during continued inspiration. The VRG, believed to be the site of rhythmic inspiratory drive. located within the ventrolateral medulla, contains More recent research in animal models suggests both inspiratory and expiratory neurons. VRG that the respiratory rhythm is generated by a group output increases in response to the need for forced of cells known as the pre-Bo¨ tzinger complex, expiration occurring during exercise or with a network of cells surrounding the Bo¨ tzinger com- increased airways resistance. Respiratory effec- plex in the ventrolateral medulla.2 tors muscles are innervated from the VRG via The medullary centers respond to direct influ- phrenic, intercostal, and abdominal motoneurons. ences from the upper airways, intra-arterial chemo- Poorly understood pontine influences further receptors, and lung afferents via the fifth, ninth regulate and coordinate inspiratory and expiratory and tenth cranial nerves, respectively. The DRG control. The pneumotaxic center in the rostral Fig. 1. A simplified diagram of the principal efferent (left) and afferent (right) respiratory control pathways. A section through the brain, brain stem, and spinal cord is shown (with pertinent respiratory areas indicated by shading), as are the central nervous system links with the respiratory apparatus. (Netter illustration from http://www.netterimages.com. Ó Elsevier Inc. All rights reserved.) 500 Malik et al pons consists of the nucleus parabrachialis and low PaO2 is markedly attenuated in the setting of the Kolliker-Fuse nucleus. This area appears to low PaCO2. primarily influence the duration of inspiration and Respiratory responses to increases in central provide tonic input to respiratory pattern genera- PaCO2 levels above 28 mm Hg are linear with tors. Similarly, the apneustic center, located in increases in respiratory rate, tidal volume, and 4 the lower pons, functions to provide signals that minute ventilation. Peripheral PaCO2-driven smoothly terminate inspiratory efforts. The pontine responses also vary with differences in levels of input serves to fine-tune respiratory patterns and PaO2. By contrast, the slope of the ventilatory may additionally modulate responses to hyper- response to PaO2 varies based on sensitivity and capnia, hypoxia, and lung inflation.3 The automatic threshold. The response to hypoxia is nonlinear central control of respiration may be influenced and appears to be minimal above PaO2 levels of and temporarily overridden by volitional control 60 mm Hg. from the cerebral cortex for a variety of activities, Resultant interactions of chemoreceptor inputs such as speech, singing, laughing, intentional regulate normal PaCO2 levels in humans to and psychogenic alterations of respiration, and between 37 and 43 mm Hg at sea level. In effect, breath holding. respiratory control is primarily dependent on Afferent input to the central controllers is PaCO2 with modulation by other factors. Sensitivity mediated primarily by central chemoreceptors, of peripheral receptor responses to hypercapnia peripheral chemoreceptors, intrapulmonary re- and hypoxia also increases with a reduction in ceptors, and chest-wall/mechanoreceptors. Che- arterial pH. Whereas acute hypoxia stimulates moreceptors provide a direct feedback to central increased sensitivity to PaCO2 peripherally, it might controllers in response to the consequences of depress central respiratory drive.5 altered respiratory efforts. Central chemorecep- Additional feedback to the central controller is tors, located primarily within the ventrolateral transmitted from the lung directly from pulmonary surface of medulla, respond to changes in brain stretch receptors (PSRs) and other afferent extracellular fluid [H1] concentration. Other pathways. PSRs are located in proximal airway receptors have been recently identified in the smooth muscles, and respond to inflation, brainstem, hypothalamus, and the cerebellum. especially in the setting of hyperinflation. PSRs These receptors are effectively CO2 receptors, mediate a shortened inspiratory and prolonged as central