In mammals, respiratory activity is under the control of both of the respiratory gases. In general, carbon dioxide seems to be the principal gas concerned, but oxygen also plays an important role. The primacy of carbon dioxide control is, however, so great that there is substantial possibility for error in coupling respiratory activity to oxygen intake. Some disturbances which result from such errors will be discussed in Part 4.

     In evaluating the role of carbon dioxide in respiratory regulation, it should always be remembered that carbon dioxide combines with water to form carbonic acid. This acid, H₂CO₃, is a weak acid, that is to say, it does not ionize very completely to form the hydrogen ion (H⁺). Nevertheless, it does ionize to a certain extent. The importance of the fact that carbonic acid ionizes to form hydrogen ions gives carbon dioxide two ways to "signal" the respiratory centers. It may do so as itself, or it may do so by changing the hydrogen ion concentration. Probably both are used.

2. Nervous Control of Respiration:

     There are two sets of respiratory muscles. Those of the lungs (bronchial) are smooth muscles and are autonomically controlled. The muscles which enlarge and diminish the size of the chest--and therefore the size of the lung--are all striated muscles. Like other striated muscles, they do not contract unless their nerves are stimulated, so when their nerves are cut they become paralyzed and atrophy. Their neuromuscular junctions, like those of striated muscles elsewhere, are blocked by curane.

     The bronchial muscles, like other smooth muscles, maintain a functional autonomy, and the denervated lung does not show bronchial atrophy. These muscles are responsive to the autonomic transmitter agents. Thus, epinephrine and epinephrine-like compounds cause them to relax (bronchodilation), while para-sympathomimetic agents cause them to constrict. It seems probable that every inspiration is coupled with autonomically mediated bronchodilatation, while expiration is associated with autonomically mediated bronchial constriction.

     The striated muscles which change the size of the chest are ordinarily moved without conscious effort; despite this, they cannot function at all in the absence of the central nervous system. The contrast with, say, the heart, or the intestine, both of which maintain spontaneous movements after all their nervous connections have been severed puts the "automatic" activity of respiration into a class of its own. In the next part of this chapter, we shall consider how this "automatic" activity is governed.

     Briefly, it may be said that co-ordinated respiration requires that a variety of types of information be perceived by appropriate sense organs; that these be transformed into afferent nervous information; and that the central nervous system be able to co-ordinate them; and finally issue efferent nervous impulses which supply the respiratory muscles.

     The information which is processed is of the following types:

(1) Chemical change in the blood.
(2) Information from stretch receptors in the lungs.
(3) Information from stretch receptors and other sensory receptors outside the lungs.

     The integration of this information occurs in the respiratory centers of the brain stem. These are located primarily in the medulla and the pons, but the midbrain is also involved through the reticular activating system, and the cerebral cortex can at times override all other centers. The involvement of the midbrain is almost self-evident to anyone who has watched respiration in the sleeping human, and the ability to hold one's breath or to hyperventilate deliberately speak for themselves so far as cerebral cortical control is concerned.

     The best recognized respiratory centers are in the medulla and the pons. Before describing these centers, however, it is necessary to say a word about normal breathing.

     In normal quiet breathing, the inspiratory act requires that muscles be activated. Expiration occurs without muscular effort. The deformations produced in the lungs and the chest wall by the act of inspiration are reversed when inspiratory effort ceases. This type of respiration could be brought about solely by an inspiratory pacemaker, which like the cardiac pacemaker is discharged intermittently, becomes inactive during its repolarization, and is discharged spontaneously sometime later. Very probably just such a mechanism governs normal quiet breathing. However, unlike the cardiac pacemaker, the inspiratory pacemaker appears to be made of a complicated neuronal system which has the added capability of bringing about active expiration. The medullary centers actually contain neurons which can be shown to cause either inspiration or expiration when stimulated. These neurons are somewhat separated anatomically though intermingled functionally.

     These medullary centers alone are quite capable of maintaining the respiratory cycle in animals in which the higher centers are separated from the medulla. The respiratory activity of such animals is irregular and spasmatic. Both inspiration and expiration appear to be active processes in these animals. This suggests that the neurons may be reciprocally connected, so that inspiratory discharge brings about inspiratory inhibition and expiratory excitation, while expiratory effort brings about expiratory inhibition and expiratory excitation. The cyclic nature of this process is self-evident.

     As noted, this respiration is spasmatic and irregular. A smoother type of respiration is observed when the brain stem is transected through the pons and includes a center called the apneustic center. This center acts to stimulate inspiratory activity at a rate greater than that seen in the medullary oscillations. The center supplies an inspiratory drive so powerful that it may overide the reciprocal innervation between inspiration and expiration and actually lead to death in the inspiration position. This occurs when the vagus nerves are cut, a maneuver which deprives the apneustic center of sensory information from lhe lungs. The importance of this information is that inspiration and inspiratory activity must be terminated and replaced by expiratory activity.

     A center in the upper part of the pons can also operate to inhibit the apneustic center and to promote expiratory activity. This center is called the pneumotoxic center.

     The coordinated activity of the medullary and pontive centers are influenced by chemical changes in the blood as well as the activity of various stretch receptors, resulting in respiratory responses indetectably different from the normal. Before considering these respiratory responses in detail, it will be necessary to say a few words concerning the receptor organs, the afferent and efferent pathways.

     The receptor organs concerned with respiration can be divided into two groups: chemoreceptors, organs sensitive to chemical change, and mechanoreceptors, organs sensitive to mechanical change.

     The identified chemoreceptors are located in the carotid and aortic bodies and in the brain itself. Those in the carotid and aortic body are small structures located on the carotid sinuses and aortic arch and are similarly innervated. They appear to be stimulated by reduction in the partial pressure of oxygen in the arterial blood and to a smaller extent by increases in the partial pressure of carbon dioxide. The chemoreceptors of the brain itself were once all believed to be particularly sensitive to the partial pressure of carbon dioxide, but it now appears probable that some of these chemoreceptors are stimulated by changes in H⁺ ion concentration rather than CO₂ as such. It will be recalled from Part 1 that carbonic acid forrned from CO₂, though a weak acid, contributes to the H⁺ ion concentration). The hydrogen ion receptors appear to be dominated by the cerebrospinal fluid by which they are usually bathed. The medullary inspiratory centers, the apneustic and the pneumotoxic, appear to be more dominated by the partial pressure of carbon dioxide than by H⁺ ion concentration. However, this statement cannot be made with complete assurance. Carbon dioxide moves very rapidly across cell membranes; after it enters a cell it must alter the cellular concentration of hydrogen ion (See also Chapter 23). It may be reemphasized here that regardless of the mechanism, there is little doubt that the partial pressure of CO₂ somehow influences the respiratory centers.

     The important mechanoreceptors are located in the lungs themselves and in muscles, tendons and joints throughout the body. Those in the lungs are of two types. Some respond to hyperinflation of the lungs; the stimulus is converted into an afferent vagal impulse which inhibits the apneustic center. Others, less easily activated, respond to extreme expiration. These too convey impulses to the central nervous system, probably by way of the vagus, but perhaps also by way sympathetic sensory fibers. The central representation of these receptors is unknown.

Peripheral mechanoreceptors:

     Increased ventilation begins in exercise before there has been time for the blood from the exercising tissue to reach the chemoreceptors or the respiratory centers. This suggests that the increased respiratory needs of exercise can be anticipated, presumably by impulses arising from peripheral mechanoreceptors. This belief received strong reenforcement when it was found that passive bending of the limbs (where someone else does the work) leads to increased ventilation. An interesting variation of this effect may be seen when one rides what is in effect a motor driven bicycle. Though the subject does no real work, a few minutes on such a device leaves most people quite breathless.

     Of late, the significance of the responses to peripheral mechanoreceptors has been less and less emphasized. At the present time, it is not clear whether these receptors play a major role in respiratory adjustments, or how they do it if they do it.

Efferent Pathways for Respiration:

     The nerves that control quiet respiration are the phrenic and intercostal nerves. The phrenic nerves, which leave the cord in the cervical region (C2-4) each supply one half of the diaphragm. The intercostal muscles receive their nerve supply from the thoracic segments of the cord. Both sets of nerves are coordinated in the brain stem.

     During maximal respiratory effort, the muscles supplied by these nerves are supplemented by the muscles of the neck and face as well as of the abdomen and shoulder girdle. The tortured expression of the marathon runner attests not so much to his agony as to the use of facial and neck muscles in the fight for air. Sympathetic discharge further contributes to air exchange by reducing the resistance of the respiratory passages.

3. Synthesis of Chemical and Neural Factors in the Control of Respiration:

     The preceding sections of this chapter may become more meaningful if the elements of respiratory control are put together in describing how ventilation is regulated in the resting individual and what changes occur during exercise. At rest the lungs are in midposition. The inspiratory act occurs 16-18 times per minute as the result of the activity of the inspiratory pacemaker. The tidal air is some 400 to 500 ml; the ending of inspiratory activity is brought about by neuronal factors, which presumably inhibit the inspiratory act centrally, perhaps through the pneumotoxic center. During inspiration, the resistance of the airway is reduced as the result of sympathetic discharge to bronchiolar muscles. At the same time, the lungs are put on the stretch, the chest is deformed, and the abdominal organs are displaced. Expiration follows passively.

     The respiratory activity described is about right to ventilate the alveoli enough so that the partial pressure of carbon dioxide in the pulmonary capillaries is adjusted to the normal level; the partial pressure of oxygen is similarly adjusted. If the ventilation is deficient, oxygen partial pressure will fall a little, while that of CO₂ will rise. The fall in oxygen will stimulate the aortic and carotid bodies, the rise in carbon dioxide will stimulate the central chemoreceptors, some directly, some by way of hydrogen ion changes. All these together will result in one or two exaggerated inspirations which correct the deficient ventilation. These may be seen as a sigh or a yawn.

     If, now, activity is begun, proprioceptive impulses from the active joints acting on the respiratory centers cause more and deeper ventilation. This is soon followed by the arrival at the lung of oxygen-deficient, CO₂-rich blood. Arterial blood, momentarily equilibrated with the altered alveolar air, reaches the carotid and aortic bodies, which are stimulated by the lack of oxygen, and immediately afterwards the medullary and pontive respiratory centers which are stimulated by carbon dioxide directly. All together, these act to increase the rate and duration of discharge of the inspiratory center. Breathing becomes deeper and more frequent.

     But not too deep. Great inspiratory effort stimulates the stretch receptors of the lung and inhibits the act of inspiration. This is called the Hering-Breuer reflex. Expiration succeeds at once; eventually the rate and depth of respiration are both increased. Meanwhile, the slightly increased arterial CO₂ reaches the cerebral circulation, diffusing across the choroid plexuses. The cerebrospinal fluid is made more acid and the H⁺ sensitive areas are triggered to support the respiratory centers in their increased activity.

     The whole process is so effective that in the end, the alveolar air comes to be of the same composition during exercise as it was before exercise. Arterial blood shows the same partial pressure of CO₂ and O₂ as it did before exercise. It seems legitimate to ask what now maintains increased respiratory activity.

     The answer, surprisingly, is not known. Many physiologists respond to the question by saying that alveolar ventilation is maintained at supra-normal levels because if it were not, the blood gases would restimulate supranormal activity. This argument appears reasonable, but it loses its force when examined closely. Physical, chemical and physiological systems do not look into a variety of hypothetical futures and adjust in such a manner as to ward off the undesirable ones. They must operate on available information. The available information in exercise is that the blood gases are quite normal, so if the story so far has been told correctly, this should result in respiratory activity which is also quite normal, or perhaps, a little less than what was required.

     It may be suspected that not all the necessary information is available. Perhaps exercise, invoking the activity of the sympathetic nervous system and catecholamim release, resets the receptors so that normal blood gases are not recognized as normal. Perhaps the reticular activating system does the same. The whole problem deserves and is receiving considerable attention.

     There is some fairly good evidence that the receptors which control respiration can be reset. In sleep, these receptors are exposed to partial pressures of carbon dioxide which are much higher than normal, yet respiratory activity is reduced. It appears that the afferent activity of the receptors is increased by efferent activity from the waking brain and decreased in the sleeping brain. Other examples of resetting will be considered next.

4. Abnormal Respiratory Patterns:

     A number of abnormal respiratory patterns will be considered here, but no attempt will he made to cover all of them.

a. Respiration in Emphysema:

     In emphysema, the exchange surface of the lung is insufficient to produce the necessary gas transfers. Further, the destruction of elastic tissue in the lung leads to a reversal of the normal pattern of effort in respiration. Emphysematous persons must work to exhale though inspiration is easy. The deficiency in the exchange surface develops slowly as the inter-alveolar septa are obliterated (Figure 278). In the course of time, the respiratory centers accommodate to the characteristic increase in arterial CO₂. The carotid and aortic bodies may accommodate to decreased oxygen, but breathing is always a distressing process because the emphysematous subject apparently never accommodates to the need for active expiration, normally a passive process. The outlook is extremely poor both because of the relentless progression of the disease and the sufferings which will be endured by the patient.

b. Respiration in Diabetic Acidosis:

     It will be seen later that diabetics not treated with insulin tend to produce strong acids. These react with the HCO₃ ion of blood to produce H₂CO₃. The carbonic acid raises the H⁺ ion concentration. Some dissociates to form CO₂ and water. Both the H⁺ ion and CO₂ act as respiratory stimulants. Characteristically the person in diabetic acidosis may be adequately oxygenated.

c. Hyperventilation:

     Some organic cerebral diseases lead to profound and continued hyperventilation. Oxygenation in the lungs is normal; for some reason the chemoreceptors appear to be reset for a lower level of CO₂ and H⁺ ion than is normal. Prolonged hyperventilation, removing CO₂ from the tissues, may lead to an inability to transfer oxygen from the blood to the tissues, since CO₂ is required to unload oxygen from oxy-hemoglobin in the tissues effectively (Chapter 18).

     Hyperventilation often occurs in persons without organic disease, sometimes as the result of emotional disturbances. This may produce a great number of unpleasant symptoms and should always be considered in a patient whose complaints do not fit any obvious illness. The diagnosis and treatment are gratifyingly simple. The diagnosis is made by having the patient hyperventilate deliberately. This usually exaggerates the symptoms of which he has been complaining. The treatment, directed to the cause (carbon dioxide deficiency) may be either rebreathing from a paper bag, which is only moderately effective, or making the patient aware of the fact that he is hyperventilating unconsciously and instructing him to hold his breath deliberately after each yawn or sigh.

d. Altitude Sickness:

     Severe, sometimes fatal, respiratory failure may occur after sudden exposure to high altitude. The low partial pressure of oxygen increases the ventilation rate through its action on the aortic and carotid bodies. This results in hyperventilation, which eliminates carbon dioxide from the already low body stores. The carbon dioxide level may become so low that the respiratory centers sensitive to CO₂ and H⁺ ions fail to respond. The respiratory responses to carbon dioxide are much more powerful than those to oxygen lack. A person in the situation described may fail to breathe despite low oxygen in the arterial blood because his carbon dioxide is even lower.

     A very dramatic example of this is seen in persons who rebreathe air from which the carbon dioxide is removed by an absorbent agent, usually sodium hydroxide or soda lime. As rebreathing goes on, the oxygen falls but carbon dioxide does not rise. The respiratory stimulus having disappeared, respiration stops. Although oxygen falls even lower, the occasional breath taken does not supply enough oxygen to sustain life, and in a short time the medullary centers die. This fortunately rare sequence of events is not usually attended by respiratory distress--actually, persons breathing poorly oxygenated air appear to enjoy it (Medical students at one time used to go on nitrous oxide, laughing gas, jags. These were probably more effective because of their low oxygen concentration rather than their high nitrous oxide concentration. Fatalities were not uncommon. This illustrates well how much better the respirator system is fashioned for the elimination of carbon dioxide than the intake of oxygen.

     Many anesthetic agents (and alcohol) appear to impair the ability of brain tissue to use oxygen. By the same token, they reduce cerebral carbon dioxide production. If the respiratory centers are affected, they suffer doubly. Lacking the ability to use oxygen they hover on the verge of dying. If in addition the decreased production of carbon dioxide fails to supply an adequate respiratory stimulus, the initial oxygen deficit is compounded by respiratory failure. Many anesthetic deaths are due to respiratory failure brought about in this manner.

e. The Lungs in Left Heart Failure:

     Left heart failure tends to result in the accumulation of blood in the lungs. Even without pulmonary edema, this results in decreased pulmonary distensibility. As the lungs inflate, the Hering-Brever reflex is excited and inspiration is terminated. Not only is it difficult to breathe because of the increased amount of lung-blood mass, but inspiration becomes self limited. The combination leads to labored breathing dyspnea.

     Carbon Monoxide Poisoning reduces the capacity of the blood to carry oxygen but not the partial pressure of oxygen. The hypoxic chemoreceptor stimulus is therefore not invoked. Carbon dioxide transport is essentially normal; if anything, there is less carbon dioxide to be moved than was the case normally, the reduced oxygen delivery leading to reduced CO₂ production. It requires very little time for the respiratory centers to fail, depending on the carbon monoxide concentration of the air. See also Chapter 18.

f. Periodic Breathing:

     There are a number of types of periodic breathing. The most interesting, usually seen in very ill patients, is called Cheyne-Stokes breathing. Such breathing begins with a burst of hyperventilation which lowers alveolar CO₂ and raises alveolar oxygen. The combined effect is to remove the chemical stimulus to respiration, and respiration stops, apnea.

     During the apnea, carbon dioxide builds up in the alveolar air, and oxygen falls. The rise in carbon dioxide provokes respiratory activity in the medullary and pontive centers, but more carbon dioxide than normal is necessary because the fall in oxygen which has occured during apnea has diminished the sensitivity of the centers, which become unresponsive to CO₂. Respiratory activity does not begin until the carbon dioxide is very high indeed. Oxygen, at the same time, is very low and the centers become even more insensitive. The peripheral chemoreceptors, stimulated by the low oxygen, "arouse" the central chemoreceptors to the point where they are activated by CO₂. A few breaths now occur. They relieve the hyperapnea (high CO₂) and the hypoxia and so put an end to respiratory activity. Again CO₂ rises while oxygen falls. The fall in oxygen again desensitizes the brain stem centers to CO₂ and a new period of apnea ensues. When it is terminated, the respiratory centers discharge again; again CO₂ is lowered and oxygen elevated; again apnea supervenes. In some patients this sequence may lead to irreparable damage to the cerebral respiratory centers, and they may become totally insensitive to hyperapnea because they are hypoxic. Hypoxia, though it remains a stimulus for the aortic and carotid bodies, is ineffective because the dying brain stem has become unresponsive to signals from the peripheral chemoreceptors. In other patients, the periods of apnea become shorter and shorter, and eventually normal breathing replaces the Cheyne-Stokes periodicity. The pattern of Cheyne-Stokes breathing in a normal patient who has hyperventilated is shown in Figure 279. Oxygen and carbon dioxide levels are indicated.

Continue to Chapter 20.