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Annals o f Biomedical Engineering, Vol. 9, pp. 395-407, 1981 Printed in the USA. All rights reserved.

0090-6964/81/050395-13 $02.00[0 Copyright 9 1982 Pergamon Press Ltd.


Neil S. Cherniack and Guy S. Longobardo Department of Medicine Case WesternReserveUniversity Cleveland,Ohio

Arterial blood gas tensions are maintained at appropriate levels through a feedback system which adjusts ventilation and has multiple inputs and outputs. Inputs to the system arise mainly from peripheral and central chemoreceptors, but there are other inputs from mechanoreceptors and higher brain centers. Output from the system travels to chest wall and upper airway muscles. Need to conserve energy consumption by the respiratory system may also affect controller activity. The response times o f the system may be important clinically but are not measured by conventionally used tests o f respiratory control. Instability in respiratory control may contribute to the recurrent periods o f apnea seen during sleep.

A feedback control system adjusts ventilation so as to maintain arterial PCO 2 and PO 2 constant (1, 14, 18). Clinically this constancy o f blood gas tensions is so well accepted that deviations in blood gas tensions from "normal limits" for any sustained period of time are t h o u g h t to indicate some serious abnormality in the respiratory system. In fact, blood gas tensions can vary considerably from "normal limits" for short periods o f time because adjustments in ventilation are not instantaneous and because the operation of the respiratory control system can be modified or even overridden temporarily by higher brain centers. The ability o f the control system to correct disturbances in blood gas tensions caused by volitional or metabolic changes depends both on the properties o f the respiratory controller and the plant that it regulates. Elucidation o f these characteristics has been a subject o f intensive investigation although much remains to be determined (13, 20, 30). Supported by N.I.H.grants, HL-25830and AG-01403, and V.A. MeritReview. Address correspondence to Neil S. Cherniack, Department of Medicine, University Hospitals, 2074 AbingtonRoad, Cleveland,Ohio 44106.



Neil S. Cherniak and Guy S. Longobardo

Figure 1 is a schematic representation of the chemically controlled respiratory system. This system can be considered to be composed of a controlled system and a controller (14). The controlled system consists of the lung, the chest wall, the respiratory muscles, and the CO2 and 02 contained in chemical combination and physical solution in the blood and body tissues (the body stores of 02 and CO2). The controller consists of the bulbopontine respiratory neurons which cause the usually regular sequence of inspiration and expiration; and chemoreceptors which respond to changes in the level of PCO2, PO2, and pH in their immediate locale. Although this review will deal mainly with the chemical regulation of breathing, it should be noted that the respiratory pattern and the level of breathing can be substantially modified by inputs unrelated to changes in PCO2 or PO2. For example, inputs originating from receptors in the limbs and from the cortex may help adjust ventilation to changes in metabolic rate, and allow ventilation to increase over broad limits during exercise with little or no change in arterial PCO2 (39).

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FIGURE 1. Schematic representation of respiratory control system. Dotted lines indicate neural pathways. Bulbopontine neurons activate respiratory muscles producing ventilation. Ventilation by determining the amount of 02 taken into the body and the CO 2 removed affect the amount of the 02 and CO 2 stored in the body, the level of PCO2, PO2, and H + in the regions of operation of chemoreceptors and hence their excitation, Chemoreceptor activity in turn helps modify the activity of the bulbopontine neurons which generate the respiratory rhythm. The activity of the neurons is also influenced by mechanoreceptors, higher brain centers, and possibly by receptors in exercising muscle.

Chemical Control o f Respira~'on


OPERATION OF THE CHEMICAL CONTROL SYSTEM: THE CONTROLLER Rhythmic breathing seems to depend on interactions between groups of neurons located in the medulla (5, 18, 41). Two groups of neurons have been described: A dorsal group located in the vicinity of the nucleus tractus solitarius (NTS) which has an important influence on phrenic motor activity and hence on diaphragm contraction; and a ventral group in the nucleus retroambigualis (NRA) and nucleus ambigualis (NA). Efferent activity of the cranial nerves which supply upper airway muscles is adjusted by NA activity, and the discharge of inspiratory intercostal and expiratory muscles by the NRA. The activity of these medullary groups of respiratory neurons can be altered by input from pontine and suprapontine areas. In addition, there are pathways which bypass these medullary neuronal networks and allow respiratory muscles to be volitionally controlled (35). The operating point at which arterial PCO 2 and PO2 are maintained seems to depend on the sleep-waking cycle (9, 25, 27, 34). Arterial PCO 2 seems to be somewhat higher and arterial PO 2 somewhat lower in the deeper stages of slow wave sleep than it is during wakefulness (27, 34). Changes in the level of arterial PO2 are detected by peripheral arterial sensors in the cartid bifurcation (the carotid body) and near the aortic arch (the aortic body). When stimulated they have both respiratory and circulatory effects and are one of the links by which the ventilatory and vasomotor responses are coordinated (2, 32). In humans the carotid body appears to be mainly responsible for the increase in ventilation observed with hypoxia. The exact mechanism which allows the carotid body to respond to changes in PO 2 is still under study. It may depend on energy producing reactions sensitive to hypoxia in these peripheral arterial sensors (1, 2). The ventilatory response to hypoxia depends crucially on the level of arterial PCO2 (11, 19, 28). Increasing PCO2 multiplies the ventilatory response to hypoxia as shown in Fig. 2. Some of this multiplicative effect occurs at the carotid body which by itself accounts for 10% to 50% of the response to hypercapnia even under hyperoxic conditions (1, 37). An additional multiplication of hypoxic and hypercapnic inputs may take place centrally as well (22, 28). The carotid body also responds to the swings in arterial PCO2 that occur with inspiration (3, 36). Increases in the amplitude of these swings seem to stimulate carotid body activity. Carotid body discharges appear to produce a greater effect in ventilation when the peak of the swing in their activity coincides with inspiration (24). Hence, the action of the carotid body on ventilation may be affected by changes in the circulation time between that sensor and the lung. There seems to be inhibitory efferent nerves from the brain which affect carotid body output (33). Alkalosis of the cerebrospinal fluid is reported to increase efferent inhibition (31).


Neil S. Cherniak and Guy S. Longobardo


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FIGURE 2. Ventilatory responses to hypercapnia, on the left; and hypoxia, on the right. PCO2 and 02 are expressed in mm Hg, and ventilation in liters per minute. With hypoxia, AV/APC02 increase. With increasing hypercapnia the ventilatory response to hypoxia increases.

The carotid body responds to changes in arterial PCO 2 and PO2 within a few seconds, but the remaining ventilatory response to CO2 occurs much more slowly over minutes. This additional ventilation, which makes up 50% to 90% of the total CO2 response, seems to originate in receptors located in the medulla that respond to changes in PCO2 or H + in their immediate environment (probably the interstitial fluid surrounding them) (1,4, 16, 29). This means that they will be affected by the rapid changes in PCO2 that occur in arterial blood as well as the slower changes in PCO2 in the cerebrospinal fluid. Neither the anatomic location nor how these receptors sense the CO 2 signal is known. However, it is clear that the activity of these receptors can be affected by manipulations in temperature and in acidity confined to the ventrolateral surface of the medulla (16). It may be that the central chemoreceptors themselves are located at these superficial sites. Ventilation lowers interstitial fluid pH by changing PCO 2 levels in the blood perfusing the brain. The ventilatory response to CO 2 is linear over a wide range of CO2 tensions (Fig. 2). However, hypoxia increases the slope of the line relating ventilation to PCO 2 and hence seems to behave as if it increases the gain of the CO2 controller (18, 22, 28). In anesthetized and sleeping animals and humans there may be some threshold level of CO2 needed to initiate breathing (17, 21, 25, 16, 27, 34). This threshold PCO2 is decreased by hypoxia and also seems to be reduced by increased activity of the respiratory muscles (11, 23). For example, voluntary hyperventilation even to extremely low levels of PCO2 fails to produce apnea, while passive hyperventilation can cause breathing to stop in the unconscious subject (23, 25). Acidosis in the arterial blood seems to increase ventilation at any given level of PCO2 while alkalosis has the reverse effect. Severe acidosis seems to

Chemical Control o f Respiration


also increase the slope of the ventilatory CO2 response line, while severe alkalosis depresses it (19). Impulses from the central peripheral chemoreceptors in humans affect both the frequency of breathing and the amount of air inspired and expired with each breath (the tidal volume) and hence set the level of ventilation (18, 19). In anesthetized animals, changes in breathing frequency seen under conditions of increased chemical drive depend on the activity of pulmonary stretch receptors innervated by the vagus which respond to changes in lung volume (5, 18, 41). The time needed for signal transmission from neurons in the medulla and muscle contraction is very short and is in the order of milliseconds.
THE CONTROLLED SYSTEM While the diaphragm seems to be the major muscle of inspiration, the respiratory controller also affects discharges in nerves supplying other inspiratory and expiratory muscles and hence can affect the efficiency of the energy utilized in breathing. More importantly, the negative intrathoracic pressures generated by diaphragm contraction can occlude the upper air passages in sleeping humans unless the muscles of the upper airway are appropriately stimulated so that they can oppose this obstructing force (6, 34, 38). The threshold drives needed to activate upper airway muscles are not the same as those needed to activate the muscles of the chest so that disturbances in ventilation, particularly those that reduce chemical drive below usual levels, may result in upper airway obstruction (6, 7). Hence, the adequacy of ventilation and its time course is affected by how controller drive is distributed to different muscle groups. There is some evidence that central and peripheral chemoreceptor input are not distributed in the same way to upper airway muscles like the tongue and muscles of the chest wall like the diaphragm (7). Ventilation alters the gas stores of the body (the amount of CO2 contained in physical solution and chemical combination) and, as a consequence, blood and tissue levels of PCO2 and PO2 (13). Only a small amount of 02 is stored in the body and this is mainly in the blood where 02 is combined with hemoglobin and in the air in the functional residual capacity of the lung. Hence, large and abrupt changes in arterial PO2 are produced by ventilation changes. If breathing is stopped for one minute, PaO2 will fall from about 100 to 40-50 mm Hg. On the other hand, much more CO2 is stored in the body mainly in the form of bicarbonate in the soft tissues and in the form of carbonate in the bone. If all the body's capacity to store CO2 were immediately available, PCO 2 would rise by only 1 to 2 mm Hg each minute even if there were no breathing. Dynamically the CO2 stores of the body behave as if they were contained in multiple compartments arranged in parallel and interconnected via the circulation. Hence, CO2 exchange in tissues seems to be limited by perfusion; equilibration of CO 2 between the


Nell S. Cherniak and Guy S. Longobardo

blood and poorly perfused tissues may be extremely slow requiring hours. Because of limited perfusion PCO 2 will increase 6 to 8 mm Hg in the first minute of breath-hold but still far less than the corresponding fall in PO 2 (13, 30). The dynamics of storage equilibration can affect the speed with which respiratory adjustments occur. High cardiac output increases the speed with which arterial and mixed venous blood gas levels can be restored to usual levels following a disturbance (30). Likewise, increasing the rate of perfusion to muscles accelerates the change in arterial PCO2 during exercise, when muscle metabolism is increased and seems to increase the rapidity of ventilation changes (39). The dynamics of CO2 storage in the brain where the central chemoreceptors are located are particularly important in determining the dynamics of the response to CO2 (7, 13). Active buffering by the brain, as well as active and passive mechanisms which affect H+ exchange between the brain and the blood, keep CSF acidity more constant than that of the arterial blood (1, 4). Also, increases in cerebral blood flow which occur with hypoxia and hypercapnia minimize changes in interstitial fluid acidity (1,4). The speed with which peripheral and central chemoreceptors receive information of changes in PCO2 and PO2 at the lung depends on the cardiac output. The higher the cardiac output, the less the circulation time and the faster the transfer of information. Changes in the controller as well as in the stores affect the dynamics of ventilatory control. In general, increasing controller gain or the PCO 2 set point accelerates the speed with which disturbances in blood gas tensions can be corrected (20). However, the need for rapid responses and for swiftly minimizing blood gas changes must be balanced against the risks of increasing the energy costs of breathing and unstable ventilatory control (9, 14, 17, 30). For example, increased controller sensitivity allows CO 2 stores to be returned more rapidly to normal levels after a disturbance like breath holding which raises arterial PCO 2 . But since the rate of CO2 elimination from the body is limited by perfusion, increasing controller sensitivities has a decreasing effect on CO2 removal (9). On the other hand, increasing controller sensitivity raises ventilation and the 02 cost of breathing, hence the 02 cost of removing a given amount of CO2 may change reaching some minimum as controller sensitivity is increased from very low to very high values. These energy considerations become very important when the 02 cost of breathing is very high, as they are in some patients with pulmonary disease. Since both speed of response and energy cost change with alterations in controller sensitivity, the sensitivity of the controller may be optimized in these patients. This optimization may involve a "Figure of Merit" defined as the ratio of liters of CO2 expelled per liter 02 consumed in breathing (30). When the O2 cost of breathing is high, the Figure o f Merit peaks at a controller sensitivity of 1.5 liter/min/mm Hg (Fig. 3).

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F I G U R E 3. Effect of controller sensitivity on Figure of Merit: (a) (upper left) when steady state PaCO 2 = 40 mm Hg and cardiac output = 5 L/rain; (b) (lower left) when PaCe 2 = 40 mm Hg and cardiac output = 50 L/min; (c) (upper right) when PaCO 2 = 80 mm Hg and cardiac output = 5 L/rain; (d) (lower right) when controllers receive central and peripheral chemoreceptor input as compared to when controllers receive peripheral chemoreceptor input only. All graphs show values when energy costs are calculated by E = V3 (broken line) and E - I/2 + 0.01V 3 (solid line). [Data from Longobardo e t al. (30)].




Control theory predicts that instability will occur in a system when controller gain is increased sufficiently, there are excessive delays in information transfer, or system damping is too low (8). Instability can occur in the respiratory control system and produces Cheyne-Stokes breathing. This is characterized by cyclic rises and falls in ventilation frequently accompanied by periods of apnea. Frequently it is also associated with cyclic variations in other physiological systems. For example, blood pressure and heart rate rise and fall with ventilation, and the state of arousal is greater during the period of hyperventilation (21): It used to be believed that Cheyne-Stokes breathing occurred only in patients with severe neurologic disease which altered controller characteristics or with profound congestive heart failure which led to prolonged circulation times. It is now recognized that similar waxing and waning of breathing can occur in sleeping individuals, as shown in Fig. 4, who have no obvious nervous system disease or evidence of circulatory failure (9, 27, 34). The gain of the respiratory controller can be considered to be the slope of the line relating ventilation to changes in PC02 or P02. Ventilation increases


Neil S. Cherniak and Guy S. Longobardo


20 seconds

FIGURE 4. Record of periodic breathing in a sleeping human. Upper trace, air flow, and lower trace, rib cage displacement. Breathing waxes and wanes but apnea is obstructive since there is no air flow even though rib cage movement continues.

linearly as PCO2 is raised so that controller gain is unaffected by increasing hypercapnia. However in unconscious humans, there is a threshold PCO 2 below which apnea occurs (8, 25). This threshold produces an alinearity in CO 2 control. During sleep both threshold and resting PCO 2 are elevated and the ventilatory CO2 response line is shifted to the right, as shown in Fig. 5 (26, 34). The elevation in threshold PCO 2 allows apnea to occur readily during sleep. Because the amount of CO2 expired depends both on alveolar ventilation and alveolar PCO 2 (usually the same as arterial PCO2 ), more CO2 will be expired for a given ventilation change when PCO2 is high as in sleep than when it is lower as it is in wakefulness. Hence arterial PCO2 will reach threshold valued more easily (20). The hypoxia that occurs during apneic periods is an important factor affecting stability. Since the relation between hypoxia and ventilation is nearly hyperbolic, increases in controller gain occur continuously and at an increasingly greater rate as hypoxia becomes more severe. Also the small amount of 02 stored in the body allows small ventilation changes to produce large changes in PaO2 and this increases the predisposition to oscillations in ventilation. These tendencies toward instability are further aggravated if a slowing of circulation time occurs (9, 14). Apnea during sleep has been classified as central, i.e., absent respiratory activity; and obstructive, no air flow despite continued respiratory activity (9, 27, 34). Obstructive apnea seems to occur as a result of upper airway occlusion during sleep. Recurrent central apneas frequently resemble CheyneStokes breathing and may be caused by the increase in resting arterial PCO2 and shifts in the controller curves occurring during sleep. Episodes of obstructive apnea, as shown in Fig. 4, may have a similar waxing and waning pattern of ventilation. One idea of the genesis of obstructive apnea is as follows. Sleep diminishes the activity of upper airway

Chemical Control o f Respiration






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FIGURE 5. Example of the shift in ventilatory response to CO2 occurring in quiet sleep [data from Gothe etal. (26).]

muscles more than it decreases the activity of chest wall muscles (34, 38). This disproportionate change in the relative activity of the two sets of muscles leads to upper airway obstruction. Arousal terminates the period of obstruction by increasing once again upper airway muscle activity. Another possibility is that obstructive apnea like central apnea is a manifestation of respiratory controller instability (9). Just as the activity of chest wall muscles waxes and wanes during Cheyne-Stokes breathing, a similar cyclic fluctuation occurs in the activity of upper airway muscles. Because the two sets of muscles differ in their responses to chemical stimulation, the two oscillations may not be exactly in phase (15). This would produce periods of both central and obstructive apnea during sleep. It would also explain why the ventilatory pattern, when obstructive apneas occurs is sometimes less regular than that observed during classic Cheyne-Stokes breathing. Since some of the upper airway muscles seem to have a higher PCO2 threshold than the diaphragm, it is likely that many apneas will be mixed in type. At the beginning upper airway air flow will be absent because of the disappearance of all respiratory activity (central apnea) and later air flow will be absent because of obstruction. This is in fact the breathing pattern frequently reported in sleep apnea (27, 34). The obstructed period, because it intensifies the hypoxia that occurs during apneic phase, may increase the instability of breathing. As might be predicted from this view of the genesis of obstructive apnea, tracheostomy to relieve the upper airway obstruction does not prevent the occurrence of periods of central apnea (40). Based on the above


Neil S. Cherniak and Guy S. Longobardo

considerations, a mathematical model which successfully simulates many of the apneic episodes during sleep has been proposed (15). In the model, the controlled system consists of multiple body compartments interconnected by the circulation. A dead space is also included in the model. The activity of chest wall and upper airway muscles is considered to vary sinusoidally during a breath. The activity of both sets of muscles is considered to depend on peripheral and central chemoreceptors. The activity of the chest wall muscles increases linearly with hypercapnia and hyperbolically with hypoxia (19). The model contains a threshold level of PCO2 and PO 2 below which apnea occurs. CO 2 and 0 2 drives are considered to multiply each other nonlinearly. The response of the upper airway muscles have both a tonic and a phasic inspiratory component which varies exponentially (in agreement with our own studies in animals) with changes in PCO 2 at central and peripheral chemoreceptors (7). The exponent increasing the CO2 response of the upper airway muscles varies nonlinearly with hypoxia similar to that of the chest wall muscles. The controller curves for both chest wall and upper airway muscles are considered to shift to the right during sleep and the tonic activity of the upper airway muscles is considered to decrease. If at any time during breathing controller drive to the chest wall muscles exceeds that to the upper airway muscles, obstructive apnea is considered to occur. Shifting the controller curve sufficiently to the right (raising the P C O 2 threshold) initiates a period of central apnea following which cyclic variations occur in gas tension and in both chest wall and upper airway muscles. Because of the dissimilarities in the responses of the two sets of muscles to chemical stimuli, the characteristics of the oscillations are not the same, as shown in Fig. 6. At times obstructive apneas occur when chest wall muscle activity exceeds upper airway muscle activity; at other times there is little activity in either muscle set producing a central apnea. Note that the cycles are not precisely regular because of the interaction between chest wall and upper airway muscle activity in determining ventilation. Oscillations of the type shown in Fig. 6 can also be produced by lengthening the circulation time, or by decreasing the tonic activity of the upper airway muscles. These changes decrease the extent to which the controller curves need to be shifted to the right to produce the instability.

METHODS OF ASSESSING THE CHEMICAL CONTROL OF BREATHING Conventionally used methods of evaluating the chemical control of breathing involve the inspiration of gases low in 0 2 or enriched in CO 2 until a steady state is reached. These tests are extremely time consuming. More recently rebreathing methods which are easier to perform have been developed to assess the ventilatory response to hypercapnia under hyperoxic conditions and the response to hypoxia under isocapnia conditions (10, 12, 19).



of Respiration


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FIGURE 6. Periodic breathing in sleep simulated by a mathematical modal. Time after onset of sleep is shown on the horizontal axis. The model includes central and peripheral chemoreceptors, 0 2 and CO2 effects on chest wall and upper airway muscles, and a multicompartmant of the body gas stores. A fuller description of the modal is given in (15). Upper t w o panels, changes in arterial blood gas tensions. Third panel, changes in the electrical activity of chest wall muscles like the diaphragm, shown by solid line, and the activity of upper airway muscles like the tongue, shown by broken line. Lowest panel, changes in tidal volume. Central apnees occur when chest wall activity falls to zero. Obstructive apnaa occurs when the activity of upper airway muscles is less than the activity of the diaphragm.

Using these tests patients are evaluated by determining the relationship between ventilation and changes in PCO 2 and PaO2. The curvilinear ventilatory response to hypoxia can be linearized by plotting ventilation against changes in arterial 02 saturation. This linearization is fortuitous and should not be taken to mean that changes in 02 saturation directly affect peripheral chemoreceptor output (19). These tests of chemosensitivity have been criticized on several grounds. For example, inhalation of CO2 is an unnatural stimulus in the sense that it rarely if ever occurs except in laboratory situations. During rebreathing tests, ventilatory responses are measured at very high levels of PCO 2 far from those usually observed even in patients with disease. In addition, ventilatory responses to chemical changes are affected by changes in the mechanical properties of the lung and thorax so that breathing through a resistance applied at the m o u t h may by itself lower ventilatory response to hypercapnia and hypoxia. Ways of assessing respiratory m o t o r o u t p u t changes other than by ventilation which use electromyographic signals from respiratory muscles or respiratory force have been tried to meet this criticism. Behavioral and psychological effects have been shown to modify responses


Neil S. Cherniak and Guy S. Longobardo

to hypoxia and hypercapnia so these tests cannot be considered just as measures o f chemosensitivity alone (12). The wide scatter observed in these tests even when normal individuals are studied probably is due in part to these behavioral effects. Finally, these tests measure at best only controller gains. Tests are also needed to determine the dynamics o f the respiratory system since it is the total system dynamics that determine h o w rapidly life threatening disturbances in PCO 2 and PO 2 can be corrected. REFERENCES
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