Respiration is controlled to maintain arterial gas pressures at appropriate levels, to minimize the work of breathing, and to alter respiration transiently for conscious activities (e.g., speech), reflexes (e.g., sneezing), and voluntary acts (e.g., blowing and breath holding).
14.1 Central Control of Respiration
Medullary Respiratory Center
Regular quiet breathing is directed by interacting groups of neurons in the medulla (Fig. 14.1). Neurons located in diffuse groups in the dorsal and ventral regions of the medulla act as pattern generators whose activity waxes and wanes during each breathing cycle. Efferent neurons rhythmically stimulate motoneurons in the spinal cord, whose peripheral axons exit in spinal nerves and travel in the phrenic nerve to the diaphragm and in other nerves to reach the accessory muscles of ventilation.
The activity of the medullary pattern generators is modulated by many inputs.
Parallel pathways originating in the cerebral cortex take over control of the spinal motoneurons during voluntary control of breathing.
Drugs causing respiratory depression
Barbiturates, benzodiazepines, and opioids are all known to cause respiratory depression. Barbiturates and benzodiazepines act by facilitating the effects of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS), at the α subunit of the GABAA receptor. Opioids act at μ receptors throughout the body, the effects of which can be both excitatory and inhibitory. These drugs depress the response of the medullary respiratory center to hypercapnia (↑ CO2), leading to respiratory depression.
Cheyne-Stokes and Kussmaul breathing
Cheyne-Stokes breathing is characterized by the absence of breathing (apnea) followed by an increased rate of ventilation (hyperventilation). It is caused by a delayed response of respiratory neurons to changes in the partial pressures of oxygen (Po2) and carbon dioxide (Pco2), which may occur when there is hypoperfusion of the brain or when hypoxic drive is regulating respiration.
Kussmaul breathing is characterized by regular deep breathing that occurs (appropriately) in response to metabolic acidosis (e.g., diabetic ketoacidosis; see box page 282).
Inputs that Modulate Respiration
Ventilation is normally adjusted to maintain arterial Pco2 close to a set point of 40 mm Hg. Excursions from the set point occur under many conditions that then excite or inhibit respiratory neurons to increase or decrease ventilation (Fig. 14.2).
The primary detection of arterial Pco2 occurs via chemoreceptors in the floor of the fourth ventricle in the brainstem.
– CO2 from the blood equilibrates with the cerebrospinal fluid (CSF) so that any change in arterial Pco2 causes a change in CSF Pco2. This also causes a change in CSF pH; for example, a rise in arterial Pco2 causes a drop in CSF pH (CO2 + H2O ⇆ H+ + HCO3−). In response, the chemoreceptive neurons, which are sensitive to pH, stimulate neurons in the medullary respiratory center to increase ventilation. A lowering of arterial Pco2 (causing ↑ pH) results in inhibition of the medullary respiratory center.
Chemoreceptive neurons in the carotid bodies (located at the bifurcation of the internal and external carotid arteries) and aortic bodies (on the arch of the aorta) respond to changes in arterial Pco2, Po2, and pH and send afferent impulses to the medullary respiratory centers via the glossopharnygeal and vagus nerves, respectively (Fig. 14.1). The carotid body chemoreceptors are the most important peripheral chemoreceptors.
– The carotid body chemoreceptors are not sensitive to small changes in arterial Po2 in well-oxygenated blood but markedly increase their stimulation of the respiratory centers as arterial Po2 falls below 60 mm Hg, a situation called hypoxic drive.
Fig. 14.1 Respiratory control and stimulation.
The medullary rhythm generator (s) repetitively excite spinal motoneurons involved in ventilation. Their activity is modulated by feedback from central chemoreceptors, which respond to changes in the Pco2 and pH of cerebrospinal fluid (CSF); peripheral chemoreceptors, which respond to changes in Pco2, pH, and Po2 in the blood; mechanoreceptors, which respond to stretching of intercostal muscles to modulate the depth of breathing; and higher centers, which modulate the basic rhythm of respiration during times of emotion, during reflexes (e.g., coughing or sneezing), and during voluntary control of respiration (e.g., while speaking or singing). During physical work, the total ventilation increases due to coinnervation of the respiratory centers by collaterals of cortical efferent motor fibers and through impulses transmitted by proprioceptive fibers from the muscles.
Fig. 14.2 Modulators of respiratory neurons.
Many factors have excitatory and inhibitory effects on respiratory neurons that then increase or decrease ventilation accordingly.
– An increase in arterial PCO2 and a fall in pH will activate peripheral chemoreceptors, resulting in an increase in respiratory rate. Likewise, when arterial PCO2 falls and arterial pH rises, their stimulation decreases.
– Peripheral chemoreceptors respond more quickly than central chemoreceptors to sudden changes in PCO2, but are not required for the long-term maintenance of arterial Pco2. Thus peripheral chemoreceptors serve as rapid detectors of changes in Pco2, while central chemoreceptors play a major role in keeping arterial Pco2 at a normal steady-state value.
Other Receptors that Modulate Respiration
– There are receptors in the walls of the bronchi that respond to inhaled irritants (e.g., dust, pollen, and chemicals) and trigger reflexes such as coughing and sneezing.
Pulmonary stretch receptors
– There are a variety of stretch receptors in the smooth muscle of the bronchial tree that influence the medullary respiratory center. These receptors are responsible for the Hering–Breuer reflex, which exerts an inhibitory influence as the lungs inflate, thereby limiting the depth of respiration.
Muscle and joint receptors
– Muscle and joint receptors are activated during exercise and trigger an increase in ventilation.
14.2 Response of the Respiratory System to Exercise and High Altitude
– The onset of exercise causes a rapid initial increase in depth and frequency of breathing, followed by a slower secondary rise. The precise triggers for increased ventilation are unknown but are thought to involve receptors in activated muscles and joints, an increase in body temperature, conscious awareness of exercise, and other cerebral cortical activation.
– During prolonged exercise, a ventilatory plateau is reached, representing a steady state. Ventilation is matched to increased metabolic demands of exercise (↑O2 consumption and ↑CO2 production).
– During exercise, there is an increase in pulmonary blood flow due to an increase in cardiac output. There is adequate time for gas exchange despite this increased pulmonary blood flow.
– The ventilation/perfusion (V/Q) ratio progressively increases during exercise because ventilation increases more than cardiac output (and therefore pulmonary blood flow). The ratio may reach 4:1.
– Po2, Pco2, and pH are maintained at levels of a resting person during light to moderate cardiovascular exercise. At peak cardiovascular exercise, anaerobic respiration causes lactic acid buildup in blood. This causes arterial pH to drop and stimulation of central chemoreceptors, leading to an increase in respiratory rate and subsequent decrease in Pco2.
– After cessation of exercise, respiratory rate only gradually returns to resting values while lactic acid is metabolized (repayment of the “oxygen debt”).
– At high altitudes, barometric pressure and therefore alveolar Po2 are decreased, resulting in decreased arterial Po2 (hypoxemia) and hypoxia. The severity of hypoxia is proportional to the altitude.
– Immediate hypoxemia stimulates peripheral chemoreceptors, producing an acute increase in the ventilation rate (hyperventilation) and an increase in the V/Q ratio. This hyperventilation then causes a respiratory alkalosis that is corrected by renal compensatory mechanisms after several days (see Chapter 18).
– Hypoxemia also stimulates hypoxic vasoconstriction in the lungs. This increases pulmonary vascular resistance and may lead to right heart failure secondary to pulmonary hypertension (cor pulmonale).
– Acclimatization occurs with prolonged exposure to high-altitude conditions.
– Hypoxemia stimulates the release of renal erythropoietin, which stimulates bone marrow to increase production of red blood cells (polycythemia). This results in an increase in hemoglobin concentration and a larger O2 transport capacity. However, polycythemia leads to an increase in the hematocrit (percentage of blood volume that is red blood cells) after 1 to 2 weeks and increased blood viscosity.
– Increased production of 2,3-diphosphoglycerate (2,-3-DPG) causes a shift of the hemoglobin–O2 dissociation curve to the right, which facilitates the unloading of O2 in the tissues at a given Po2.
Acute mountain sickness
Acute mountain sickness is often seen with rapid changes from sea level to 10,000 ft (3000 m). If severe, hypoxic stimulation of the entire lung causes hypoxic vasoconstriction throughout pulmonary vessels and a large increase in pulmonary artery pressure, leading to high-altitude pulmonary edema (HAPE). Cerebral edema may also occur. Symptoms include headache, malaise, nausea, vomiting, dizziness, shortness of breath (dyspnea), and increased heart rate (tachycardia). Treatment involves descending to a lower altitude as soon as possible and O2 administration. HAPE is treated with nifedipine (a calcium-channel blocker) or sildenafil (a phosphodiesterase inhibitor). Dexamethasone is used for cerebral edema.