Respiratory Physiology During Sleep BY AHMAD YOUNES PROFESSOR OF THORACIC MEDICINE Mansoura Faculty of Medicine The respiratory system provides continuous homeostasis of PaO2, PaCO2, and pH levels during constantly changing physiologic conditions. This elegant system responds promptly to subtle variations in metabolism occurring in both health and disease. During wakefulness, volitional influences can override this automatic control. Modifications occur in the regulation and control of respiration with the onset of sleep. Furthermore, these changes differ significantly with specific sleep stages. Consequences of these alterations of respiratory control can result in the pathogenesis of sleep-related breathing disorders and limit the usual respiratory compensatory changes to specific disease states. Most patients who have arterial oxygen desaturation in the sleep center do so from apnea or hypopnea. Patients with respiratory disorders may have sleep- related arterial oxygen desaturation and/or hypoventilation without a significant number of discrete apnea or hypopnea events These abnormalities in gas exchange can occur because the normal effects of sleep on ventilation and oxygenation are magnified by abnormal function of the lung, chest wall, respiratory muscles, or ventilatory control centers. NORMAL CHANGES IN VENTILATION DURING SLEEP Sensors primarily include central and peripheral chemoreceptors, vagal pulmonary sensors, and chest wall and respiratory muscle afferents. Data from these sensors regarding dynamic oxygen and CO2 levels, lung volumes, and respiratory muscle activity are continuously transmitted to the central controller. Within the medulla, the central controller generates an automated rhythm of respiration that is constantly modified in response to an integrated input from the various receptors. The controller modulates motor output from the brainstem to influence the activity of the effectors, namely respiratory motoneurons and muscles. These effectors then alter minute ventilation and gas exchange accordingly. The central pattern generator is composed of predominately three neuronal groups 1- Drsal respiratory group 2- Ventral respiratory group 3- Pontine respiratory group. The dorsal respiratory group is in the ventrolateral subnucleus of the nucleus tractus solitarius. This neuronal group is primarily active during inspiration receiving input from pulmonary vagal afferents. Many of these neurons excite lower motor cranial nerves that dilate the upper airway prior to excitation of the contralateral phrenic and intercostal neurons in the spinal cord. This coordinated output must occur in the correct timed sequence to permit the movement of air through a patent airway. Ventral respiratory group The ventral respiratory group is located in the ventral lateral medulla from the top of the cervical cord to the level of the facial nerve. This group contains the Botzinger complex, the preBotzinger neurons, the rostral portion of nucleus ambiguous, and nucleus retroambigualis. The Botzinger complex contains neurons that are active during expiration and inhibit inspiration. The preBotzinger complex contains propriobulbar neurons that participate in generating the rhythm of respiration. The caudal portion of this group is primarily composed of expiratory neurons that project to intercostal, abdominal, and external sphincter motor neurons. Ventilatory control The medullary centers respond to direct influences from the upper airways, intra-arterial chemoreceptors, and lung afferents by the 5th, 9th, and 10th cranial nerves, respectively. The dorsal respiratory group seems to be active primarily during inspiration. The ventral respiratory group, contains both inspiratory and expiratory neurons. Ventral respiratory group output increases in response to the need for forced expiration occurring during exercise or with increased airways resistance. Respiratory effector muscles are innervated from the ventral respiratory group by phrenic, intercostal, and abdominal motoneurons. Pontine respiratory centers The pneumotaxic center in the rostral pons consists of the nucleus parabrachialis and the Kolliker-Fuse nucleus. This area seems primarily to influence the duration of inspiration and provide tonic input to respiratory pattern generators. The apneustic center, located in the lower pons, functions to provide signals that terminate smoothly inspiratory efforts. The pontine input serves to fine tune respiratory patterns and may additionally modulate responses to hypercapnia, hypoxia, and lung inflation. The automatic central control of respiration may be influenced and temporarily overridden by volitional control from the cerebral cortex for a variety of activities, such as speech, singing, laughing, intentional and psychogenic alterations of respiration, and breath holding. Central chemoreceptors Central chemoreceptors, located primarily within the ventrolateral surface of medulla, respond to changes in brain extracellular fluid [H1] concentration. Other receptors have been recently identified in the brainstem, hypothalamus, and the cerebellum. These receptors are effectively CO2 receptors because central [H1] concentrations are directly dependent on central PCO2 levels. Central [H1] may differ significantly from arterial [H1] because the blood-brain barrier prevents polar solute diffusion into the cerebrospinal fluid. This isolation results in an indirect central response to most peripheral acid- base disturbances mediated through changes in PaCO2. Central responses to changes in PCO2 levels are also slightly delayed for a few minutes by the location of receptors in the brain only, rather than in peripheral vascular tissues. Peripheral chemoreceptors Peripheral chemoreceptors include the carotid bodies and the aortic bodies. The carotid bodies, located bilaterally at the bifurcation of the internal and external carotid arteries, are the primary peripheral monitors. They are highly vascular structures that monitor the status of blood about to be delivered to the brain and provide afferent input to the medulla through the 9th cranial nerve. The carotid bodies respond mainly to PaO2, but also to changes in PaCO2 and pH. They do not respond to lowered oxygen content from anemia or carbon monoxide toxicity. Other afferent pathways Pulmonary stretch receptors are located in proximal airway smooth muscles, and respond to inflation, especially in the setting of hyperinflation. Pulmonary stretch receptors mediate a shortened inspiratory and prolonged expiratory duration. Additional input is also provided by rapidly adapting receptors that sense flow and irritation. J receptors are located in the juxtacapillary area and seem to mediate dyspnea in the setting of pulmonary vascular congestion. Bronchial c-fibers also affect bronchomotor tone and respond to pulmonary inflammation. Other afferent pathways Afferent activity from chest wall and respiratory muscles additionally influences central controller activity. Feedback information regarding muscle stretch, loading, and fatigue may impact both regulatory and somato-sensory responses. Upper airway receptors promote airway patency by activation of local muscles including the genioglossus. During sleep During sleep, the metabolic rate falls (hence, decreased CO2 production), but this is offset by a proportionately greater fall in minute ventilation with the result that the PaCO2 increases slightly. The fall in ventilation is due to increased upper airway resistance and decreased chemosensitivity as well as the loss of the wakefulness stimulus to breathe. The result is that the PaCO2 rises and the PaO2 falls slightly Because of the normal position on the flat portion of the O2Hb dissociation curve, there is little change in the SaO2 as a result of the fall in PO2 associated with sleep. If the baseline awake PaO2 is lower, the fall in SaO2 will be greater for the same drop in PaO2. In patients with lung disease and a lower awake PO2, even a normal sleep-related drop in PO2 will be associated with a larger decrease in the SaO2. The change in ventilation with sleep is due to a fall in Vt with minimal change in the RR. During the transition from wake to stage N1 and early stage N2, the ventilation can be slightly irregular. However, in stable stage N2 and stage N3, the Vt and RR are nearly constant. During REM sleep, ventilation is irregular with periods of decreased Vt associated with bursts of eye movements. The FRC decreases from wake to sleep. During sleep, the hypercapnic ventilatory response and hypoxic ventilatory response are reduced during NREM compared with wake and decreased in REM sleep compared with NREM sleep. Both hypoxia and hypercapnea may trigger arousals from sleep, resulting in a return to the more tightly regulated ventilatory control associated with wakefulness. Arousal thresholds for hypercapnia range between 65 and 66 mmHg and do not vary consistently among the different sleep stages. The threshold for arousal in response to hypoxia is more variable and seems less reliable. Severe oxygen desaturations in some individuals do not uniformly result in arousals. Alveolar hypoventilation Alveolar hypoventilation during wakefulness is defined as an PaCO2 of 45 mm Hg or higher. If the sleeping PaCO2 is 10 mm Hg above the awake value, Sleep hypoventilation is said to be present. Hypoxemia is defined as a low arterial partial pressure of oxygen (PaO2) relative to predicted values. A PaO2 < 55 mm Hg while breathing room air is considered severe and an indication for chronic 24-hour supplemental oxygen therapy. Milder degree of hypoxemia can be identified by comparing a PaO2 with a predicted value for age. A simple estimate of a normal predicted PaO2 Pao2=105 1/2 age (yr). Alveolar gas equation The alveolar gas equation allows one to compute the alveolar (ideal) partial pressure of oxygen (PAO2) from the fractional concentration of oxygen in inspired gas (FIO2), which is 0.21 when breathing room air,and the PaCO2. The respiratory exchange ratio (R) is the CO2 elimination divided by the O2 uptake. At steady state, R is equal to 0.8. Computation of the PAO2 and the A-a gradient PAO2 = FIO2(PB - PH2 O) - PaCO2/R R=VCO2/VO2 ( assumed to be 0.8) VCO2= CO2 elimination. VO2 = O2 uptake FIO2 = 0.21 (breathing room air), PB is the barometric pressure (760 mm Hg at sea level), and PH2O is the partial pressure of water vapor (47 mm Hg at 37C). Alveolar gas equation The A-a gradient is the difference between the ideal PAO2 and the actual (measured) PaO2. (usually