Guyton and Hall Textbook of Medical Physiology, 12th Ed

CHAPTER 41

Regulation of Respiration

imageThe nervous system normally adjusts the rate of alveolar ventilation almost exactly to the demands of the body so that the oxygen pressure (PO2) and carbon dioxide pressure (PCO2) in the arterial blood are hardly altered, even during heavy exercise and most other types of respiratory stress. This chapter describes the function of this neurogenic system for regulation of respiration.

Respiratory Center

The respiratory center is composed of several groups of neurons located bilaterally in the medulla oblongata and pons of the brain stem, as shown in Figure 41-1. It is divided into three major collections of neurons: (1) a dorsal respiratory group, located in the dorsal portion of the medulla, which mainly causes inspiration; (2) a ventral respiratory group, located in the ventrolateral part of the medulla, which mainly causes expiration; and (3) the pneumotaxic center, located dorsally in the superior portion of the pons, which mainly controls rate and depth of breathing.

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Figure 41-1 Organization of the respiratory center.

Dorsal Respiratory Group of Neurons—Its Control of Inspiration and of Respiratory Rhythm

The dorsal respiratory group of neurons plays the most fundamental role in the control of respiration and extends most of the length of the medulla. Most of its neurons are located within the nucleus of the tractus solitarius (NTS), although additional neurons in the adjacent reticular substance of the medulla also play important roles in respiratory control. The NTS is the sensory termination of both the vagal and the glossopharyngeal nerves, which transmit sensory signals into the respiratory center from (1) peripheral chemoreceptors, (2) baroreceptors, and (3) several types of receptors in the lungs.

Rhythmical Inspiratory Discharges from the Dorsal Respiratory Group

The basic rhythm of respiration is generated mainly in the dorsal respiratory group of neurons. Even when all the peripheral nerves entering the medulla have been sectioned and the brain stem transected both above and below the medulla, this group of neurons still emits repetitive bursts of inspiratory neuronal action potentials. The basic cause of these repetitive discharges is unknown. In primitive animals, neural networks have been found in which activity of one set of neurons excites a second set, which in turn inhibits the first. Then, after a period of time, the mechanism repeats itself, continuing throughout the life of the animal. Therefore, most respiratory physiologists believe that some similar network of neurons is present in the human being, located entirely within the medulla; it probably involves not only the dorsal respiratory group but adjacent areas of the medulla as well, and it is responsible for the basic rhythm of respiration.

Inspiratory “Ramp” Signal

The nervous signal that is transmitted to the inspiratory muscles, mainly the diaphragm, is not an instantaneous burst of action potentials. Instead, it begins weakly and increases steadily in a ramp manner for about 2 seconds in normal respiration. Then it ceases abruptly for approximately the next 3 seconds, which turns off the excitation of the diaphragm and allows elastic recoil of the lungs and the chest wall to cause expiration. Next, the inspiratory signal begins again for another cycle; this cycle repeats again and again, with expiration occurring in between. Thus, the inspiratory signal is a ramp signal. The obvious advantage of the ramp is that it causes a steady increase in the volume of the lungs during inspiration, rather than inspiratory gasps.

There are two qualities of the inspiratory ramp that are controlled, as follows:

1. Control of the rate of increase of the ramp signal so that during heavy respiration, the ramp increases rapidly and therefore fills the lungs rapidly.

2. Control of the limiting point at which the ramp suddenly ceases. This is the usual method for controlling the rate of respiration; that is, the earlier the ramp ceases, the shorter the duration of inspiration. This also shortens the duration of expiration. Thus, the frequency of respiration is increased.

A Pneumotaxic Center Limits the Duration of Inspiration and Increases the Respiratory Rate

pneumotaxic center, located dorsally in the nucleus parabrachialis of the upper pons, transmits signals to the inspiratory area. The primary effect of this center is to control the “switch-off” point of the inspiratory ramp, thus controlling the duration of the filling phase of the lung cycle. When the pneumotaxic signal is strong, inspiration might last for as little as 0.5 second, thus filling the lungs only slightly; when the pneumotaxic signal is weak, inspiration might continue for 5 or more seconds, thus filling the lungs with a great excess of air.

The function of the pneumotaxic center is primarily to limit inspiration. This has a secondary effect of increasing the rate of breathing because limitation of inspiration also shortens expiration and the entire period of each respiration. A strong pneumotaxic signal can increase the rate of breathing to 30 to 40 breaths per minute, whereas a weak pneumotaxic signal may reduce the rate to only 3 to 5 breaths per minute.

Ventral Respiratory Group of Neurons—Functions in Both Inspiration and Expiration

Located in each side of the medulla, about 5 millimeters anterior and lateral to the dorsal respiratory group of neurons, is the ventral respiratory group of neurons, found in the nucleus ambiguus rostrally and the nucleus retroambiguus caudally. The function of this neuronal group differs from that of the dorsal respiratory group in several important ways:

1. The neurons of the ventral respiratory group remain almost totally inactive during normal quiet respiration. Therefore, normal quiet breathing is caused only by repetitive inspiratory signals from the dorsal respiratory group transmitted mainly to the diaphragm, and expiration results from elastic recoil of the lungs and thoracic cage.

2. The ventral respiratory neurons do not appear to participate in the basic rhythmical oscillation that controls respiration.

3. When the respiratory drive for increased pulmonary ventilation becomes greater than normal, respiratory signals spill over into the ventral respiratory neurons from the basic oscillating mechanism of the dorsal respiratory area. As a consequence, the ventral respiratory area contributes extra respiratory drive as well.

4. Electrical stimulation of a few of the neurons in the ventral group causes inspiration, whereas stimulation of others causes expiration. Therefore, these neurons contribute to both inspiration and expiration. They are especially important in providing the powerful expiratory signals to the abdominal muscles during very heavy expiration. Thus, this area operates more or less as an overdrive mechanism when high levels of pulmonary ventilation are required, especially during heavy exercise.

Lung Inflation Signals Limit Inspiration—The Hering-Breuer Inflation Reflex

In addition to the central nervous system respiratory control mechanisms operating entirely within the brain stem, sensory nerve signals from the lungs also help control respiration. Most important, located in the muscular portions of the walls of the bronchi and bronchioles throughout the lungs are stretch receptors that transmit signals through the vagi into the dorsal respiratory group of neurons when the lungs become overstretched. These signals affect inspiration in much the same way as signals from the pneumotaxic center; that is, when the lungs become overly inflated, the stretch receptors activate an appropriate feedback response that “switches off” the inspiratory ramp and thus stops further inspiration. This is called the Hering-Breuer inflation reflex. This reflex also increases the rate of respiration, as is true for signals from the pneumotaxic center.

In humans, the Hering-Breuer reflex probably is not activated until the tidal volume increases to more than three times normal (>≈︀ 1.5 liters per breath). Therefore, this reflex appears to be mainly a protective mechanism for preventing excess lung inflation rather than an important ingredient in normal control of ventilation.

Control of Overall Respiratory Center Activity

Up to this point, we have discussed the basic mechanisms for causing inspiration and expiration, but it is also important to know how the intensity of the respiratory control signals is increased or decreased to match the ventilatory needs of the body. For example, during heavy exercise, the rates of oxygen usage and carbon dioxide formation are often increased to as much as 20 times normal, requiring commensurate increases in pulmonary ventilation. The major purpose of the remainder of this chapter is to discuss this control of ventilation in accord with the respiratory needs of the body.

Chemical Control of Respiration

The ultimate goal of respiration is to maintain proper concentrations of oxygen, carbon dioxide, and hydrogen ions in the tissues. It is fortunate, therefore, that respiratory activity is highly responsive to changes in each of these.

Excess carbon dioxide or excess hydrogen ions in the blood mainly act directly on the respiratory center itself, causing greatly increased strength of both the inspiratory and the expiratory motor signals to the respiratory muscles.

Oxygen, in contrast, does not have a significant direct effect on the respiratory center of the brain in controlling respiration. Instead, it acts almost entirely on peripheral chemoreceptors located in the carotidand aortic bodies, and these in turn transmit appropriate nervous signals to the respiratory center for control of respiration.

Direct Chemical Control of Respiratory Center Activity by Carbon Dioxide and Hydrogen Ions

Chemosensitive Area of the Respiratory Center

We have discussed mainly three areas of the respiratory center: the dorsal respiratory group of neurons, the ventral respiratory group, and the pneumotaxic center. It is believed that none of these is affected directly by changes in blood carbon dioxide concentration or hydrogen ion concentration. Instead, an additional neuronal area, a chemosensitive area, shown in Figure 41-2, is located bilaterally, lying only 0.2 millimeter beneath the ventral surface of the medulla. This area is highly sensitive to changes in either blood PCO2 or hydrogen ion concentration, and it in turn excites the other portions of the respiratory center.

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Figure 41-2 Stimulation of the brain stem inspiratory area by signals from the chemosensitive area located bilaterally in the medulla, lying only a fraction of a millimeter beneath the ventral medullary surface. Note also that hydrogen ions stimulate the chemosensitive area, but carbon dioxide in the fluid gives rise to most of the hydrogen ions.

Excitation of the Chemosensitive Neurons by Hydrogen Ions Is Likely the Primary Stimulus

The sensor neurons in the chemosensitive area are especially excited by hydrogen ions; in fact, it is believed that hydrogen ions may be the only important direct stimulus for these neurons. However, hydrogen ions do not easily cross the blood-brain barrier. For this reason, changes in hydrogen ion concentration in the blood have considerably less effect in stimulating the chemosensitive neurons than do changes in blood carbon dioxide, even though carbon dioxide is believed to stimulate these neurons secondarily by changing the hydrogen ion concentration, as explained in the following section.

Carbon Dioxide Stimulates the Chemosensitive Area

Although carbon dioxide has little direct effect in stimulating the neurons in the chemosensitive area, it does have a potent indirect effect. It does this by reacting with the water of the tissues to form carbonic acid, which dissociates into hydrogen and bicarbonate ions; the hydrogen ions then have a potent direct stimulatory effect on respiration. These reactions are shown in Figure 41-2.

Why does blood carbon dioxide have a more potent effect in stimulating the chemosensitive neurons than do blood hydrogen ions? The answer is that the blood-brain barrier is not very permeable to hydrogen ions, but carbon dioxide passes through this barrier almost as if the barrier did not exist. Consequently, whenever the blood PCO2 increases, so does the PCO2 of both the interstitial fluid of the medulla and the cerebrospinal fluid. In both these fluids, the carbon dioxide immediately reacts with the water to form new hydrogen ions. Thus, paradoxically, more hydrogen ions are released into the respiratory chemosensitive sensory area of the medulla when the blood carbon dioxide concentration increases than when the blood hydrogen ion concentration increases. For this reason, respiratory center activity is increased very strongly by changes in blood carbon dioxide, a fact that we subsequently discuss quantitatively.

Decreased Stimulatory Effect of Carbon Dioxide After the First 1 to 2 Days

Excitation of the respiratory center by carbon dioxide is great the first few hours after the blood carbon dioxide first increases, but then it gradually declines over the next 1 to 2 days, decreasing to about one-fifth the initial effect. Part of this decline results from renal readjustment of the hydrogen ion concentration in the circulating blood back toward normal after the carbon dioxide first increases the hydrogen concentration. The kidneys achieve this by increasing the blood bicarbonate, which binds with the hydrogen ions in the blood and cerebrospinal fluid to reduce their concentrations. But even more important, over a period of hours, the bicarbonate ions also slowly diffuse through the blood-brain and blood-cerebrospinal fluid barriers and combine directly with the hydrogen ions adjacent to the respiratory neurons as well, thus reducing the hydrogen ions back to near normal. A change in blood carbon dioxide concentration therefore has a potent acute effect on controlling respiratory drive but only a weak chronic effect after a few days’ adaptation.

Quantitative Effects of Blood PCO2 and Hydrogen Ion Concentration on Alveolar Ventilation

Figure 41-3 shows quantitatively the approximate effects of blood PCO2 and blood pH (which is an inverse logarithmic measure of hydrogen ion concentration) on alveolar ventilation. Note especially the very marked increase in ventilation caused by an increase in PCO2 in the normal range between 35 and 75 mm Hg. This demonstrates the tremendous effect that carbon dioxide changes have in controlling respiration. By contrast, the change in respiration in the normal blood pH range between 7.3 and 7.5 is less than one-tenth as great.

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Figure 41-3 Effects of increased arterial blood PCO2 and decreased arterial pH (increased hydrogen ion concentration) on the rate of alveolar ventilation.

Changes in Oxygen Have Little Direct Effect on Control of the Respiratory Center

Changes in oxygen concentration have virtually no direct effect on the respiratory center itself to alter respiratory drive (although oxygen changes do have an indirect effect, acting through the peripheral chemoreceptors, as explained in the next section).

We learned in Chapter 40 that the hemoglobin-oxygen buffer system delivers almost exactly normal amounts of oxygen to the tissues even when the pulmonary PO2 changes from a value as low as 60 mm Hg up to a value as high as 1000 mm Hg. Therefore, except under special conditions, adequate delivery of oxygen can occur despite changes in lung ventilation ranging from slightly below one-half normal to as high as 20 or more times normal. This is not true for carbon dioxide because both the blood and tissue PCO2 change inversely with the rate of pulmonary ventilation; thus, the processes of animal evolution have made carbon dioxide the major controller of respiration, not oxygen.

Yet for those special conditions in which the tissues get into trouble for lack of oxygen, the body has a special mechanism for respiratory control located in the peripheral chemoreceptors, outside the brain respiratory center; this mechanism responds when the blood oxygen falls too low, mainly below a PO2 of 70 mm Hg, as explained in the next section.

Peripheral Chemoreceptor System for Control of Respiratory Activity—Role of Oxygen in Respiratory Control

In addition to control of respiratory activity by the respiratory center itself, still another mechanism is available for controlling respiration. This is the peripheral chemoreceptor system, shown in Figure 41-4. Special nervous chemical receptors, called chemoreceptors, are located in several areas outside the brain. They are especially important for detecting changes in oxygen in the blood, although they also respond to a lesser extent to changes in carbon dioxide and hydrogen ion concentrations. The chemoreceptors transmit nervous signals to the respiratory center in the brain to help regulate respiratory activity.

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Figure 41-4 Respiratory control by peripheral chemoreceptors in the carotid and aortic bodies.

Most of the chemoreceptors are in the carotid bodies. However, a few are also in the aortic bodies, shown in the lower part of Figure 41-4, and a very few are located elsewhere in association with other arteries of the thoracic and abdominal regions.

The carotid bodies are located bilaterally in the bifurcations of the common carotid arteries. Their afferent nerve fibers pass through Hering’s nerves to the glossopharyngeal nerves and then to the dorsal respiratory area of the medulla. The aortic bodies are located along the arch of the aorta; their afferent nerve fibers pass through the vagi, also to the dorsal medullary respiratory area.

Each of the chemoreceptor bodies receives its own special blood supply through a minute artery directly from the adjacent arterial trunk. Further, blood flow through these bodies is extreme, 20 times the weight of the bodies themselves each minute. Therefore, the percentage of oxygen removed from the flowing blood is virtually zero. This means that the chemoreceptors are exposed at all times to arterial blood, not venous blood, and their PO2s are arterial PO2s.

Decreased Arterial Oxygen Stimulates the Chemoreceptors

When the oxygen concentration in the arterial blood falls below normal, the chemoreceptors become strongly stimulated. This is demonstrated in Figure 41-5, which shows the effect of different levels of arterial PO2 on the rate of nerve impulse transmission from a carotid body. Note that the impulse rate is particularly sensitive to changes in arterial PO2 in the range of 60 down to 30 mm Hg, a range in which hemoglobin saturation with oxygen decreases rapidly.

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Figure 41-5 Effect of arterial PO2 on impulse rate from the carotid body.

Increased Carbon Dioxide and Hydrogen Ion Concentration Stimulates the Chemoreceptors

An increase in either carbon dioxide concentration or hydrogen ion concentration also excites the chemoreceptors and, in this way, indirectly increases respiratory activity. However, the direct effects of both these factors in the respiratory center itself are much more powerful than their effects mediated through the chemoreceptors (about seven times as powerful). Yet there is one difference between the peripheral and central effects of carbon dioxide: The stimulation by way of the peripheral chemoreceptors occurs as much as five times as rapidly as central stimulation, so the peripheral chemoreceptors might be especially important in increasing the rapidity of response to carbon dioxide at the onset of exercise.

Basic Mechanism of Stimulation of the Chemoreceptors by Oxygen Deficiency

The exact means by which low PO2 excites the nerve endings in the carotid and aortic bodies are still unknown. However, these bodies have multiple highly characteristic glandular-like cells, called glomus cells, which synapse directly or indirectly with the nerve endings. Some investigators have suggested that these glomus cells might function as the chemoreceptors and then stimulate the nerve endings. But other studies suggest that the nerve endings themselves are directly sensitive to the low PO2.

Effect of Low Arterial PO2 to Stimulate Alveolar Ventilation When Arterial Carbon Dioxide and Hydrogen Ion Concentrations Remain Normal

Figure 41-6 shows the effect of low arterial PO2 on alveolar ventilation when the PCO2 and the hydrogen ion concentration are kept constant at their normal levels. In other words, in this figure, only the ventilatory drive, due to the effect of low oxygen on the chemoreceptors, is active. The figure shows almost no effect on ventilation as long as the arterial PO2 remains greater than 100 mm Hg. But at pressures lower than 100 mm Hg, ventilation approximately doubles when the arterial PO2 falls to 60 mm Hg and can increase as much as fivefold at very low PO2s. Under these conditions, low arterial PO2obviously drives the ventilatory process quite strongly.

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Figure 41-6 The lower curve demonstrates the effect of different levels of arterial PO2 on alveolar ventilation, showing a sixfold increase in ventilation as the PO2 decreases from the normal level of 100 mm Hg to 20 mm Hg. The upper line shows that the arterial PCO2 was kept at a constant level during the measurements of this study; pH also was kept constant.

Because the effect of hypoxia on ventilation is modest for PO2s greater than 60 to 80 mm Hg, the PCO2 and the hydrogen ion response are mainly responsible for regulating ventilation in healthy humans at sea level.

Chronic Breathing of Low Oxygen Stimulates Respiration Even More—The Phenomenon of “Acclimatization”

Mountain climbers have found that when they ascend a mountain slowly, over a period of days rather than a period of hours, they breathe much more deeply and therefore can withstand far lower atmospheric oxygen concentrations than when they ascend rapidly. This is called acclimatization.

The reason for acclimatization is that, within 2 to 3 days, the respiratory center in the brain stem loses about four fifths of its sensitivity to changes in PCO2 and hydrogen ions. Therefore, the excess ventilatory blow-off of carbon dioxide that normally would inhibit an increase in respiration fails to occur, and low oxygen can drive the respiratory system to a much higher level of alveolar ventilation than under acute conditions. Instead of the 70 percent increase in ventilation that might occur after acute exposure to low oxygen, the alveolar ventilation often increases 400 to 500 percent after 2 to 3 days of low oxygen; this helps immensely in supplying additional oxygen to the mountain climber.

Composite Effects of PCO2, pH, and PO2 on Alveolar Ventilation

Figure 41-7 gives a quick overview of the manner in which the chemical factors PO2, PCO2, and pH together affect alveolar ventilation. To understand this diagram, first observe the four red curves. These curves were recorded at different levels of arterial PO2—40 mm Hg, 50 mm Hg, 60 mm Hg, and 100 mm Hg. For each of these curves, the PCO2 was changed from lower to higher levels. Thus, this “family” of red curves represents the combined effects of alveolar PCO2 and PO2 on ventilation.

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Figure 41-7 Composite diagram showing the interrelated effects of PCO2, PO2, and pH on alveolar ventilation.

(Drawn from data in Cunningham DJC, Lloyd BB: The Regulation of Human Respiration. Oxford: Blackwell Scientific Publications, 1963.)

Now observe the green curves. The red curves were measured at a blood pH of 7.4; the green curves were measured at a pH of 7.3. We now have two families of curves representing the combined effects of PCO2 and PO2 on ventilation at two different pH values. Still other families of curves would be displaced to the right at higher pHs and displaced to the left at lower pHs. Thus, using this diagram, one can predict the level of alveolar ventilation for most combinations of alveolar PCO2, alveolar PO2, and arterial pH.

Regulation of Respiration During Exercise

In strenuous exercise, oxygen consumption and carbon dioxide formation can increase as much as 20-fold. Yet, as illustrated in Figure 41-8, in the healthy athlete, alveolar ventilation ordinarily increases almost exactly in step with the increased level of oxygen metabolism. The arterial PO2, PCO2, and pH remain almost exactly normal.

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Figure 41-8 Effect of exercise on oxygen consumption and ventilatory rate.

(From Gray JS: Pulmonary Ventilation and Its Physiological Regulation. Springfield, Ill: Charles C Thomas, 1950.)

In trying to analyze what causes the increased ventilation during exercise, one is tempted to ascribe this to increases in blood carbon dioxide and hydrogen ions, plus a decrease in blood oxygen. However, this is questionable because measurements of arterial PCO2, pH, and PO2 show that none of these values changes significantly during exercise, so none of them becomes abnormal enough to stimulate respiration so vigorously as observed during strenuous exercise. Therefore, the question must be asked: What causes intense ventilation during exercise? At least one effect seems to be predominant. The brain, on transmitting motor impulses to the exercising muscles, is believed to transmit at the same time collateral impulses into the brain stem to excite the respiratory center. This is analogous to the stimulation of the vasomotor center of the brain stem during exercise that causes a simultaneous increase in arterial pressure.

Actually, when a person begins to exercise, a large share of the total increase in ventilation begins immediately on initiation of the exercise, before any blood chemicals have had time to change. It is likely that most of the increase in respiration results from neurogenic signals transmitted directly into the brain stem respiratory center at the same time that signals go to the body muscles to cause muscle contraction.

Interrelation Between Chemical Factors and Nervous Factors in the Control of Respiration During Exercise

When a person exercises, direct nervous signals presumably stimulate the respiratory center almost the proper amount to supply the extra oxygen required for exercise and to blow off extra carbon dioxide. Occasionally, however, the nervous respiratory control signals are either too strong or too weak. Then chemical factors play a significant role in bringing about the final adjustment of respiration required to keep the oxygen, carbon dioxide, and hydrogen ion concentrations of the body fluids as nearly normal as possible.

This is demonstrated in Figure 41-9, which shows in the lower curve changes in alveolar ventilation during a 1-minute period of exercise and in the upper curve changes in arterial PCO2. Note that at the onset of exercise, the alveolar ventilation increases almost instantaneously, without an initial increase in arterial PCO2. In fact, this increase in ventilation is usually great enough so that at first it actually decreasesarterial PCO2 below normal, as shown in the figure. The presumed reason that the ventilation forges ahead of the buildup of blood carbon dioxide is that the brain provides an “anticipatory” stimulation of respiration at the onset of exercise, causing extra alveolar ventilation even before it is necessary. However, after about 30 to 40 seconds, the amount of carbon dioxide released into the blood from the active muscles approximately matches the increased rate of ventilation, and the arterial PCO2 returns essentially to normal even as the exercise continues, as shown toward the end of the 1-minute period of exercise in the figure.

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Figure 41-9 Changes in alveolar ventilation (bottom curve) and arterial PCO2 (top curve) during a 1-minute period of exercise and also after termination of exercise.

(Extrapolated to the human from data in dogs in Bainton CR: Effect of speed vs grade and shivering on ventilation in dogs during active exercise. J Appl Physiol 33:778, 1972.)

Figure 41-10 summarizes the control of respiration during exercise in still another way, this time more quantitatively. The lower curve of this figure shows the effect of different levels of arterial PCO2 on alveolar ventilation when the body is at rest—that is, not exercising. The upper curve shows the approximate shift of this ventilatory curve caused by neurogenic drive from the respiratory center that occurs during heavy exercise. The points indicated on the two curves show the arterial PCO2 first in the resting state and then in the exercising state. Note in both instances that the PCO2 is at the normal level of 40 mm Hg. In other words, the neurogenic factor shifts the curve about 20-fold in the upward direction, so ventilation almost matches the rate of carbon dioxide release, thus keeping arterial PCO2 near its normal value. The upper curve of Figure 41-10 also shows that if, during exercise, the arterial PCO2 does change from its normal value of 40 mm Hg, it has an extra stimulatory effect on ventilation at a PCO2 greater than 40 mm Hg and a depressant effect at a PCO2 less than 40 mm Hg.

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Figure 41-10 Approximate effect of maximum exercise in an athlete to shift the alveolar PCO2-ventilation response curve to a level much higher than normal. The shift, believed to be caused by neurogenic factors, is almost exactly the right amount to maintain arterial PCO2 at the normal level of 40 mm Hg both in the resting state and during heavy exercise.

Neurogenic Control of Ventilation During Exercise May Be Partly a Learned Response

Many experiments suggest that the brain’s ability to shift the ventilatory response curve during exercise, as shown in Figure 41-10, is at least partly a learned response. That is, with repeated periods of exercise, the brain becomes progressively more able to provide the proper signals required to keep the blood PCO2 at its normal level. Also, there is reason to believe that even the cerebral cortex is involved in this learning because experiments that block only the cortex also block the learned response.

Other Factors That Affect Respiration

Voluntary Control of Respiration

Thus far, we have discussed the involuntary system for the control of respiration. However, we all know that for short periods of time, respiration can be controlled voluntarily and that one can hyperventilate or hypoventilate to such an extent that serious derangements in PCO2, pH, and PO2 can occur in the blood.

Effect of Irritant Receptors in the Airways

The epithelium of the trachea, bronchi, and bronchioles is supplied with sensory nerve endings called pulmonary irritant receptors that are stimulated by many incidents. These cause coughing and sneezing, as discussed in Chapter 39. They may also cause bronchial constriction in such diseases as asthma and emphysema.

Function of Lung “J Receptors”

A few sensory nerve endings have been described in the alveolar walls in juxtaposition to the pulmonary capillaries—hence the name “J receptors.” They are stimulated especially when the pulmonary capillaries become engorged with blood or when pulmonary edema occurs in such conditions as congestive heart failure. Although the functional role of the J receptors is not clear, their excitation may give the person a feeling of dyspnea.

Brain Edema Depresses the Respiratory Center

The activity of the respiratory center may be depressed or even inactivated by acute brain edema resulting from brain concussion. For instance, the head might be struck against some solid object, after which the damaged brain tissues swell, compressing the cerebral arteries against the cranial vault and thus partially blocking cerebral blood supply.

Occasionally, respiratory depression resulting from brain edema can be relieved temporarily by intravenous injection of hypertonic solutions such as highly concentrated mannitol solution. These solutions osmotically remove some of the fluids of the brain, thus relieving intracranial pressure and sometimes re-establishing respiration within a few minutes.

Anesthesia

Perhaps the most prevalent cause of respiratory depression and respiratory arrest is overdosage with anesthetics or narcotics. For instance, sodium pentobarbital depresses the respiratory center considerably more than many other anesthetics, such as halothane. At one time, morphine was used as an anesthetic, but this drug is now used only as an adjunct to anesthetics because it greatly depresses the respiratory center while having less ability to anesthetize the cerebral cortex.

Periodic Breathing

An abnormality of respiration called periodic breathing occurs in a number of disease conditions. The person breathes deeply for a short interval and then breathes slightly or not at all for an additional interval, with the cycle repeating itself over and over. One type of periodic breathing, Cheyne-Stokes breathing, is characterized by slowly waxing and waning respiration occurring about every 40 to 60 seconds, as illustrated in Figure 41-11.

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Figure 41-11 Cheyne-Stokes breathing, showing changing PCO2 in the pulmonary blood (red line) and delayed changes in the PCO2 of the fluids of the respiratory center (blue line).

Basic Mechanism of Cheyne-Stokes Breathing

The basic cause of Cheyne-Stokes breathing is the following: When a person overbreathes, thus blowing off too much carbon dioxide from the pulmonary blood while at the same time increasing blood oxygen, it takes several seconds before the changed pulmonary blood can be transported to the brain and inhibit the excess ventilation. By this time, the person has already overventilated for an extra few seconds. Therefore, when the overventilated blood finally reaches the brain respiratory center, the center becomes depressed to an excessive amount. Then the opposite cycle begins. That is, carbon dioxide increases and oxygen decreases in the alveoli. Again, it takes a few seconds before the brain can respond to these new changes. When the brain does respond, the person breathes hard once again and the cycle repeats.

The basic cause of Cheyne-Stokes breathing occurs in everyone. However, under normal conditions, this mechanism is highly “damped.” That is, the fluids of the blood and the respiratory center control areas have large amounts of dissolved and chemically bound carbon dioxide and oxygen. Therefore, normally, the lungs cannot build up enough extra carbon dioxide or depress the oxygen sufficiently in a few seconds to cause the next cycle of the periodic breathing. But under two separate conditions, the damping factors can be overridden and Cheyne-Stokes breathing does occur:

1. When a long delay occurs for transport of blood from the lungs to the brain, changes in carbon dioxide and oxygen in the alveoli can continue for many more seconds than usual. Under these conditions, the storage capacities of the alveoli and pulmonary blood for these gases are exceeded; then, after a few more seconds, the periodic respiratory drive becomes extreme and Cheyne-Stokes breathing begins. This type of Cheyne-Stokes breathing often occurs in patients with severe cardiac failure because blood flow is slow, thus delaying the transport of blood gases from the lungs to the brain. In fact, in patients with chronic heart failure, Cheyne-Stokes breathing can sometimes occur on and off for months.

2. A second cause of Cheyne-Stokes breathing is increased negative feedback gain in the respiratory control areas. This means that a change in blood carbon dioxide or oxygen causes a far greater change in ventilation than normally. For instance, instead of the normal 2- to 3-fold increase in ventilation that occurs when the PCO2 rises 3 mm Hg, the same 3 mm Hg rise might increase ventilation 10- to 20-fold. The brain feedback tendency for periodic breathing is now strong enough to cause Cheyne-Stokes breathing without extra blood flow delay between the lungs and brain. This type of Cheyne-Stokes breathing occurs mainly in patients with brain damage. The brain damage often turns off the respiratory drive entirely for a few seconds; then an extra intense increase in blood carbon dioxide turns it back on with great force. Cheyne-Stokes breathing of this type is frequently a prelude to death from brain malfunction.

Typical records of changes in pulmonary and respiratory center PCO2 during Cheyne-Stokes breathing are shown in Figure 41-11. Note that the PCO2 of the pulmonary blood changes in advance of the Pco2of the respiratory neurons. But the depth of respiration corresponds with the PCO2 in the brain, not with the PCO2 in the pulmonary blood where the ventilation is occurring.

Sleep Apnea

The term apnea means absence of spontaneous breathing. Occasional apneas occur during normal sleep, but in persons with sleep apnea, the frequency and duration are greatly increased, with episodes of apnea lasting for 10 seconds or longer and occurring 300 to 500 times each night. Sleep apneas can be caused by obstruction of the upper airways, especially the pharynx, or by impaired central nervous system respiratory drive.

Obstructive Sleep Apnea Is Caused by Blockage of the Upper Airway

The muscles of the pharynx normally keep this passage open to allow air to flow into the lungs during inspiration. During sleep, these muscles usually relax, but the airway passage remains open enough to permit adequate airflow. Some individuals have an especially narrow passage, and relaxation of these muscles during sleep causes the pharynx to completely close so that air cannot flow into the lungs.

In persons with sleep apnea, loud snoring and labored breathing occur soon after falling asleep. The snoring proceeds, often becoming louder, and is then interrupted by a long silent period during which no breathing (apnea) occurs. These periods of apnea result in significant decreases in PO2 and increases in PCO2, which greatly stimulate respiration. This, in turn, causes sudden attempts to breathe, which result in loud snorts and gasps followed by snoring and repeated episodes of apnea. The periods of apnea and labored breathing are repeated several hundred times during the night, resulting in fragmented, restless sleep. Therefore, patients with sleep apnea usually have excessive daytime drowsiness, as well as other disorders, including increased sympathetic activity, high heart rates, pulmonary and systemic hypertension, and a greatly elevated risk for cardiovascular disease.

Obstructive sleep apnea most commonly occurs in older, obese persons in whom there is increased fat deposition in the soft tissues of the pharynx or compression of the pharynx due to excessive fat masses in the neck. In a few individuals, sleep apnea may be associated with nasal obstruction, a very large tongue, enlarged tonsils, or certain shapes of the palate that greatly increase resistance to the flow of air to the lungs during inspiration. The most common treatments of obstructive sleep apnea include (1) surgery to remove excess fat tissue at the back of the throat (a procedure called uvulopalatopharyngoplasty), to remove enlarged tonsils or adenoids, or to create an opening in the trachea (tracheostomy) to bypass the obstructed airway during sleep, and (2) nasal ventilation with continuous positive airway pressure(CPAP).

“Central” Sleep Apnea Occurs When the Neural Drive to Respiratory Muscles Is Transiently Abolished

In a few persons with sleep apnea, the central nervous system drive to the ventilatory muscles transiently ceases. Disorders that can cause cessation of the ventilatory drive during sleep include damage to the central respiratory centers or abnormalities of the respiratory neuromuscular apparatus. Patients affected by central sleep apnea may have decreased ventilation when they are awake, although they are fully capable of normal voluntary breathing. During sleep, their breathing disorders usually worsen, resulting in more frequent episodes of apnea that decrease PO2 and increase PCO2 until a critical level is reached that eventually stimulates respiration. These transient instabilities of respiration cause restless sleep and clinical features similar to those observed in obstructive sleep apnea.

In most patients the cause of central sleep apnea is unknown, although instability of the respiratory drive can result from strokes or other disorders that make the respiratory centers of the brain less responsive to the stimulatory effects of carbon dioxide and hydrogen ions. Patients with this disease are extremely sensitive to even small doses of sedatives or narcotics, which further reduce the responsiveness of the respiratory centers to the stimulatory effects of carbon dioxide. Medications that stimulate the respiratory centers can sometimes be helpful, but ventilation with CPAP at night is usually necessary.

Bibliography

Albert R., Spiro S., Jett J. Comprehensive Respiratory Medicine. Philadelphia: Mosby, 2002.

Bradley T.D., Floras J.S. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;373:82.

Datta A., Tipton M. Respiratory responses to cold water immersion: neural pathways, interactions, and clinical consequences awake and asleep. J Appl Physiol. 2006;100:2057.

Dean J.B., Ballantyne D., Cardone D.L., et al. Role of gap junctions in CO2 chemoreception and respiratory control. Am J Physiol Lung Cell Mol Physiol. 2002;283:L665.

Dempsey J.A., McKenzie D.C., Haverkamp H.C., et al. Update in the understanding of respiratory limitations to exercise performance in fit, active adults. Chest. 2008;134:613.

Eckert D.J., Jordan A.S., Merchia P., et al. Central sleep apnea: Pathophysiology and treatment. Chest. 2007;131:595.

Forster H.V. Plasticity in the control of breathing following sensory denervation. J Appl Physiol. 2003;94:784.

Gaultier C., Gallego J. Neural control of breathing: insights from genetic mouse models. J Appl Physiol. 2008;104:1522.

Gray P.A. Transcription factors and the genetic organization of brain stem respiratory neurons. J Appl Physiol. 2008;104:1513.

Guyenet P.G. The 2008 Carl Ludwig Lecture: retrotrapezoid nucleus, CO2 homeostasis, and breathing automaticity. J Appl Physiol. 2008;105:404.

Hilaire G., Pasaro R. Genesis and control of the respiratory rhythm in adult mammals. News Physiol Sci. 2003;18:23.

Horner R.L., Bradley T.D. Update in sleep and control of ventilation 2008. Am J Respir Crit Care Med. 2009;179:528.

Morris K.F., Baekey D.M., Nuding S.C., et al. Neural network plasticity in respiratory control. J Appl Physiol. 2003;94:1242.

Somers V.K., White D.P., Amin R., et al. J Am Coll Cardiol. 2008;52:686.

Sharp F.R., Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci. 2004;5:437.

Thach B.T. Some aspects of clinical relevance in the maturation of respiratory control in infants. J Appl Physiol. 2008;104:1828.

West J.B. Pulmonary Physiology-The Essentials. Baltimore: Lippincott Williams & Wilkins, 2003.

Younes M. Role of respiratory control mechanisms in the pathogenesis of obstructive sleep disorders. J Appl Physiol. 2008;105:1389.

Young T., Skatrud J., Peppard P.E. Risk factors for obstructive sleep apnea in adults. JAMA. 2004;291:2013.

 



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