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Home , Breathing, Central chemoreceptors, Diuresis, Hypercapnia, Minute ventilation, Muscles of respiration

Respiratory During

Vipin Malik, MD*, Daniel Smith, MD, Teofilo Lee-Chiong Jr, MD

KEYWORDS  Ventilatory regulation  Respiratory motoneurons    Pneumotaxic center  Apneustic center 

KEY POINTS  Ventilatory regulation is conceptually best understood as a 3-part system consisting of a central controller, sensors, and effectors.  The effectors of include the respiratory motoneurons and muscles, which are involved in inspiration and expiration.  Positional changes during sleep (ie, nonupright position) affect the mechanics of significantly.  Both hypoxemia and hypercapnia can develop during sleep in patients with chronic obstructive pulmonary disease.  Upper-airway narrowing and excess , if present, can increase the mechanical load on the as well as breathing work.

The respiratory system provides continuous CONTROL OF RESPIRATION of partial of arterial Ventilatory regulation is conceptually best under- (PaO ), (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 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, 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 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 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 Clinics Volume 5, Issue 2. Section of , National Jewish Medical and Research Center, Denver, CO, USA * Corresponding author. Section of Sleep Medicine, Division of Critical Care and , , 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 ai tal et Malik

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 , inspiration respectively Ventral Respiratory Group Ventrolateral medulla Response to the need for forced Respiratory effectors muscles are expiration occurring during innervated from the VRG via phrenic, or with increased airways resistance intercostal and abdominal motoneurons. Pneumotaxic center Rostral 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, , and lung inflation Apneustic center Lower pons Pneumotaxic center and vagal input Provide signals that smoothly terminate inspiratory efforts Ventrolateral surface of medulla [H+] Respond to changes in 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 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 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 is shown (with pertinent respiratory areas indicated by shading), as are the central 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 , , and 4 the lower pons, functions to provide signals that . 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 inputs such as , , laughing, intentional regulate normal PaCO2 levels in 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, , and the cerebellum. especially in the setting of hyperinflation. PSRs These receptors are effectively CO2 receptors, mediate a shortened inspiratory and prolonged as central [H1] are directly depen- expiratory duration. Additional input is also 1 dent on central PCO2 levels. Central [H ]may provided by rapidly adapting receptors that differ significantly from arterial [H1], as the sense flow and irritation. J-receptors are located brain barrier prevents polar solute into in the juxtacapillary area and appear to mediate the (CSF). This isolation dyspnea in the setting of pulmonary vascular results in an indirect central response to most congestion. Bronchial c-fibers also affect bron- peripheral -base disturbances mediated chomotor tone and respond to pulmonary through changes in partial of arterial inflammation. carbon dioxide (PaCO2). Central responses to Afferent activity from chest-wall and respiratory changes in PCO2 levels are also slightly delayed muscles additionally influences central controller for a few minutes by the location of receptors in activity. Feedback information regarding muscle the brain only, rather than in peripheral vascular stretch, loading, and fatigue may affect both tissues. regulatory and somatosensory responses. Peripheral chemoreceptors include the carotid Upper-airway receptors promote airway patency bodies and the aortic bodies. The carotid bodies, by activation of local muscles including the genio- located bilaterally at the bifurcation of the internal glossus. These receptors may also inhibit thoracic and external carotid , are the primary inspiratory muscle activity. Thus, afferent activity peripheral monitors. These highly vascular struc- enables an appropriate response by central tures monitor the status of blood about to be deliv- regulation. ered to the brain and provide afferent input to the The effectors of respiration include the respira- medulla through the ninth cranial nerve. The tory motoneurons and muscles, which are carotid bodies respond mainly to PaO2 but also involved in inspiration and expiration. Descending to changes in PaCO2 and pH. Of importance, they motoneurons include two anatomically separate do not respond to lowered oxygen content from groups, the corticospinal tracts and the reticulo- anemia or (CO) . Their spinal tracts. The , arising from C3 mechanisms are integrated, and acute hypoxia to C5, innervates the diaphragm as the primary induces an increased sensitivity to changes in muscle of respiration. Accessory muscles that PaCO2 and . Conversely, the response to assist inspiration include the sternocleidomastoid, Respiratory Physiology During Sleep 501

intercostal, scalene, and parasternal muscles. Ventilatory responses to CO2 and O2 differ in These muscles serve to collectively stabilize and sleep in comparison with wakefulness, with impor- expand the ribcage. Abdominal muscles are active tant distinctions between REM and NREM sleep. in expiration and may also assist with inspiration The linear increases in ventilatory responses to during exercise, or in the setting of chronic PaCO2 persist during NREM sleep, albeit with obstructive pulmonary disease (COPD) or dia- a reduced slope compared to wakefulness. These phragm weakness. Upper-airway muscles active changes appear more evident in males than in in inspiration include the genioglossus, palatal females, who demonstrate reduced CO2 muscles, pharyngeal constrictors, and muscles responses while awake with less apparent reduc- that pull the hyoid anteriorly. Collectively, these tions during NREM sleep.9 In addition, the muscle groups and motoneurons effect responses threshold of the response to CO2 is shifted generated from central control centers based on upward, with a higher ETCO2 required to drive input from multiple receptors. This elegant system respiration in sleep. Responses to increases in operates through the complex coordination and ETCO2 are further reduced during REM sleep. interaction of these subcomponents to continu- Respiratory output in sleep, particularly NREM ously adapt to changing metabolic needs. sleep, is significantly reduced in response to hypo- capnia. Respiratory responses to hypoxia appear RESPIRATION DURING SLEEP attenuated during NREM sleep as well, without significant gender-related differences; hypoxia- Regulation of respiration differs significantly induced drive is reduced further in REM sleep. between sleep and wakefulness. With sleep onset, Of importance, both hypoxia and hypercapnia important changes occur in the various processes may trigger from sleep, resulting in a re- that regulate respiratory control. Behavioral influ- turn to the more tightly regulated ventilatory ences on respiration terminate with cessation of control associated with wakefulness. input from the waking state. Positional changes thresholds for hypercapnia range between 56 typically associated with sleep also result in signif- and 65 torr, and vary among the different sleep icant alterations in respiratory mechanics. Sleep is stages. The threshold for arousal in response to a dynamic physiologic state with further varying hypoxia is more variable and seems less reliable. effects on respiration seen in specific sleep Severe oxygen desaturations in some individuals stages, particularly in rapid eye movement (REM) do not uniformly result in arousals. in comparison with non–rapid eye movement In addition to the changes in controller (NREM) sleep. responses during sleep, the effectors also demon- Minute ventilation falls with the onset of sleep strate significant sleep-related functional variation. in response to decreased metabolism and de- Of the various effectors of respiration, the upper- creased chemosensitivity to oxygen (O2) and airway muscles appear to be the most dramati- 6,7 CO2. Ventilation during NREM sleep demon- cally affected by changes occurring with sleep. strates an inherently more regular respiratory As described previously, these muscles function pattern than wakeful breathing, without significant to maintain patency and prevent collapse of the reductions in mean frequencies. The nadir of upper airways during inspiration. These muscles minute ventilation in NREM sleep occurs during primarily include the genioglossus, tensor palatini, NREM stage 3 (N3) sleep (ie, slow-wave sleep), and the sternohyoid, which are active during inspi- primarily as a result of reductions in tidal volume. ration during wakefulness and are reduced activity As a result, end-tidal carbon dioxide (ETCO2) during sleep. The genioglossus responds briskly to during NREM sleep increases by 1 to 2 torr increases in PaCO2 during wakefulness; this compared with the waking state.8 During REM response markedly diminishes during sleep. sleep, respiratory patterns and control vary more Indeed, the modest increase in PaCO2 seen with significantly. REM sleep respiration is typically sleep onset does not appear to produce a signifi- characterized by an increased frequency and cant increase in genioglossus activity. a reduced regularity. Tidal volume is reduced studies of upper-airway responses during REM further in comparison with that of NREM sleep, re- sleep are limited, with most studies demonstrating sulting in the lowest level of normal minute ventila- that muscle activity is eliminated by generalized tion. Accordingly, ETCO2 increases of an additional REM-sleep–associated atonia; 1 to 2 torr, often associated with a reduction in this effect is most prominent during phasic REM , are seen with the onset of sleep. Upper-airway responses to hypoxia gener- REM sleep. Metabolic reductions seen in sleep ally parallel the responses to hypercapnia. Studies demonstrate sleep-stage variations with increased consistently demonstrate more striking sleep- rates in REM compared to NREM sleep. related reductions in muscle activity of the upper 502 Malik et al

airways than of the diaphragm or accessory to resistance loading are more evident during . NREM sleep than in waking states. Positional changes during sleep (ie, nonupright position) affect the mechanics of breathing signifi- MEDICATIONS AND BREATHING DURING cantly. Anatomic structures of the upper airways SLEEP may be more predisposed to collapse, particularly with the concurrent reductions in upper-airway There are several drugs that can impair respiration muscle tone. Redundant soft-–related airway during sleep, including , anesthetics, compromise and retroglossal narrowing of the narcotics, and sedative hypnotics. Conversely, upper airways may be significantly increased in some agents, such as almitrine, acetazolamide, the supine position. Subtle increases in vascular some antidepressants, , , congestion of the airways in response to positional theophylline, and , can stimulate changes may also augment airways resistance. In breathing during sleep. the supine position, the contribution of chest-wall Drugs that can Impair Respiration expansion does not exceed the effect of increased abdominal distention, and functional residual Alcohol, when ingested while awake, can lead to capacity is thus reduced. Intercostal muscle reduction of both hypoxic and hypercapnic venti- activity is significantly increased during NREM latory responses. Irregular breathing with transient sleep compared with wakefulness, and results in can develop. When ingested close to proportional increases in the contribution of the , it depresses the upper-airway muscle chest wall to respiration. With REM-sleep–associ- tone and may precipitate obstructive sleep , ated atonia, skeletal muscles associated with or aggravate a preexisting one; the latter is gener- respiration are significantly impaired and ventila- ally most evident during the first 1 to 3 hours of tion is accomplished by the diaphragm alone. sleep when alcohol levels are at their highest. Chest-wall compliance is increased with this Hypercapnia and significant hypoxemia can occur decreased intercostal tone, and paradoxic with severe intoxication. The risk of sleep- collapse of the chest during inspiration may occur. disordered breathing remains elevated in some REM sleep is, therefore, associated with relative abstinent alcoholics following long-term habitual from both reduced respiratory alcohol use, possibly caused by residual upper- mechanical capacities and decreased sensitivity airway muscle dysfunction or damage to the of the respiratory drive to hypercapnia and .12 hypoxia. Anesthetics can impair the hypoxic ventilatory There are significant differences in the responses response, decrease , and decrease to increased airways resistance between sleep and upper-airway muscle tone, all of which can lead wakefulness. During the waking state, increased to significant deterioration of respiratory status in ventilatory responses to both elastic loading and patients with an existing obstructive airways-resistance loading are present; this or advanced COPD.13 prompt compensation maintains appropriate Narcotics are potent respiratory depressants ventilation and prevents development of hyper- which, when ingested at bedtime, can diminish capnia. Load compensation is significantly upper-airway muscle tone, give rise to hypox- reduced during sleep. During NREM sleep, emia, and decrease the hypercapnic ventilatory 14 moderate levels of elastic loading (18 cm H2O/L) response. results in decreases in minute ventilation and Sedative hypnotics (eg, benzodiazepines or 10 increases in ETCO2. Ventilatory effort is then barbiturates) are mild respiratory depressants. increased without normalization back to preload Depression of breathing is be more pronounced levels of ventilation. Lower levels of loading (12 during coingestion with other central nervous cm H2O/L) result in significant ventilatory changes system depressants, such as alcohol, or in individ- over a few breaths resulting in full compensa- uals with an underlying respiratory impairment tion without arousals.11 Waking responses to resis- (eg, severe COPD, neuromuscular weakness, or tance loads include an increase in the duration of hypoventilation syndromes). Both agents can respiration, an increase in tidal volume, and decrease upper-airway muscle activity and worsen a decrease in respiratory rate. Minute ventilation sleep-disordered breathing; they have variable is reduced. Responses to increased resistance effects on central apneas. Whereas they may during NREM sleep demonstrate a different pattern increase the frequency and prolong the duration of reduced tidal volumes and increased respiratory of hypercapnic forms of central apneas (eg, neuro- rates, and no significant change in inspiratory time muscular disorders), sedative hypnotics may be ratio. Reductions in minute ventilation in response beneficial for patients with certain types of Respiratory Physiology During Sleep 503 nonhypercapnic form of central apnea, such as Chronic Obstructive Pulmonary Disease those that occur periodically at sleep onset.15 Both hypoxemia and hypercapnia can develop Drugs that can Stimulate Respiration during sleep in patients with COPD. Respiratory impairment is more severe during REM sleep Almitrine is a respiratory stimulant that enhances than during NREM sleep. Hypoxemia, the extent peripheral chemoreceptor sensitivity. Although it of which is related to the percentage of REM sleep can potentially improve nighttime oxygenation, in relation to total sleep time as well as daytime 16,17 this effect is generally mild and inconsistent. levels of PaCO2,PaO2, and oxygen saturation Acetazolamide administration induces meta- (SaO2), can result from hypoventilation, ventila- bolic acidosis from ; this, in tion/ mismatching, and/or reduction of turn, can stimulate respiration.18 Although it is lung volume (eg, functional residual capacity). beneficial for the treatment of high-altitude–related COPD can also occur concurrently with obstruc- periodic breathing, its usefulness for patients with tive sleep apnea; referred to as the overlap is limited, inconsistent, syndrome; this is associated with worse hypox- and unpredictable. emia and greater pulmonary pressures Certain antidepressants, such as protriptyline, compared with patients with isolated COPD.25,26 a , and fluoxetine, a selective serotonin reuptake inhibitor, can decrease the frequency and duration of apneas- by increasing upper-airway muscle tone and decreasing Sleep of patients with interstitial lung disease is percentage of REM sleep, during which sleep- often accompanied by frequent arousals. Sleep disordered breathing tends to be worse than during disruption appears to be more pronounced in NREM sleep.19 those with nocturnal oxygen desaturation, the extent of which is influenced by levels of awake Nicotine is a respiratory stimulant. Notwith- 27 standing its effect of enhancing upper-airway PaO2, , and age of the patient. muscle activity, it has no role in the treatment of The increase in respiratory drive that is present in obstructive sleep apnea.20 patients with interstitial lung disease may reduce Progesterone can increase hypoxic and hyper- the prevalence of apneas-hypopneas. capnic respiratory responses as well as minute venti- Kyphoscoliosis, by blunting ventilatory drive due lation; it can improve ventilation in patients with to a greater mechanical load of displacing the obesity-hypoventilation syndrome and decrease thoracic cage, can lead to a number of sleep- apnea-hypopneas in post-menopausal women.21,22 related breathing disorders, such as central and Theophylline can reverse the bronchospasm of obstructive apnea-hypopneas, periodic breathing, nocturnal , increase sleep-related oxygen hypercapnia and hypoxemia. saturation in patients with COPD, and improve Obesity is associated with increased work of Cheyne-Stokes crescendo-decrescendo periodic breathing and greater metabolic demands. Lower breathing.23 functional capacity, less efficient respiratory muscles, and increased mass loading of the thoracic cage (ie, decrease in compliance) can all SLEEP PHYSIOLOGY AND RESPIRATORY give rise to hypoxemia, which is generally worse DISORDERS during sleep than during wakefulness because of Nocturnal Asthma the lower functional residual capacity of a supine Patients with nocturnal asthma often present with position, relative hypoventilation, and the develop- repetitive arousals and awakenings during the ment of sleep-related apneas-hypopneas. If night accompanied by complaints of breathless- severe, obesity can lead to the development of ness, coughing, and wheezing secondary to bron- the obesity hypoventilation syndrome with its choconstriction.24 A variety of factors may associated reductions in hypoxic and hypercapnic contribute to the worsening bronchial reactivity ventilatory drives. that occurs during sleep, including a relative , like obesity, can reduce lung volumes increase in parasympathetic tone and decrease (eg, functional residual capacity and residual in nonadrenergic, noncholinergic discharge; com- volume), especially during the third trimester when orbid gastroesophageal reflux or obstructive sleep weight gain and uterine displacement are maximal. apnea; circadian changes in levels of endogenous Pregnancy may also be associated with an increase hormones (eg, catecholamines, cortisol, or hista- in the prevalence of , owing to structural mine); or reduction of lung volumes and airway changes and increased compliance of the upper size. If severe, nocturnal asthma may give rise to airways. However, apnea- frequency and significant hypoxemia. sleep-related hypoxemia tend to be less affected 504 Malik et al

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