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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.


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). Exercising Muscles? . The controller consists of the bulbopontine respiratory neurons which cause the usually regular sequence of inspiration and expiration. 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. Cherniak and Guy S. the level of PCO2. Displacements [ Respiratory Ventilations[ 02+C02 --'-~ Muscles. Bulbopontine neurons activate respiratory muscles producing ventilation. The activity of the neurons is also influenced by mechanoreceptors. PO2. and pH in their immediate locale. Chemoreceptor activity in turn helps modify the activity of the bulbopontine neurons which generate the respiratory rhythm. This system can be considered to be composed of a controlled system and a controller (14). the respiratory muscles. Dotted lines indicate neural pathways. %.. 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. and allow ventilation to increase over broad limits during exercise with little or no change in arterial PCO2 (39). The controlled system consists of the lung. Although this review will deal mainly with the chemical regulation of breathing. Schematic representation of respiratory control system. and H + in the regions of operation of chemoreceptors and hence their excitation.. . PO2. For example. and chemoreceptors which respond to changes in the level of PCO2. and possibly by receptors in exercising muscle. Stores Chest Walls+ Lungs Peripheral I Chemoreceptors ~ Arterial Pcoz + POz Brain PCO21H + L__t Central I. higher brain centers. ChemoreceptorsF FIGURE 1. inputs originating from receptors in the limbs and from the cortex may help adjust ventilation to changes in metabolic rate. r II I Bulbapanti ne Neurons s/ Higher Centers Itt I I Mechanoreceptors] I Force.396 Neil S. the chest wall. Longobardo Figure 1 is a schematic representation of the chemically controlled respiratory system.

Efferent activity of the cranial nerves which supply upper airway muscles is adjusted by NA activity. 32). Hence. 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. and a ventral group in the nucleus retroambigualis (NRA) and nucleus ambigualis (NA). The activity of these medullary groups of respiratory neurons can be altered by input from pontine and suprapontine areas. 25. and the discharge of inspiratory intercostal and expiratory muscles by the NRA. 19. Carotid body discharges appear to produce a greater effect in ventilation when the peak of the swing in their activity coincides with inspiration (24). 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). 2. The exact mechanism which allows the carotid body to respond to changes in PO 2 is still under study. 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. It may depend on energy producing reactions sensitive to hypoxia in these peripheral arterial sensors (1. 37). 18. An additional multiplication of hypoxic and hypercapnic inputs may take place centrally as well (22. The ventilatory response to hypoxia depends crucially on the level of arterial PCO2 (11. In addition. 27. Alkalosis of the cerebrospinal fluid is reported to increase efferent inhibition (31). 41). 36). Increases in the amplitude of these swings seem to stimulate carotid body activity. 34). 34). The carotid body also responds to the swings in arterial PCO2 that occur with inspiration (3. Increasing PCO2 multiplies the ventilatory response to hypoxia as shown in Fig. 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. 2). The operating point at which arterial PCO 2 and PO2 are maintained seems to depend on the sleep-waking cycle (9. there are pathways which bypass these medullary neuronal networks and allow respiratory muscles to be volitionally controlled (35). In humans the carotid body appears to be mainly responsible for the increase in ventilation observed with hypoxia. 28).Chemical Control o f Respira~'on 397 OPERATION OF THE CHEMICAL CONTROL SYSTEM: THE CONTROLLER Rhythmic breathing seems to depend on interactions between groups of neurons located in the medulla (5. 28). 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). . 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.

22. 21. 25. voluntary hyperventilation even to extremely low levels of PCO2 fails to produce apnea. 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. Longobardo . 29). which makes up 50% to 90% of the total CO2 response. while passive hyperventilation can cause breathing to stop in the unconscious subject (23. 25). This threshold PCO2 is decreased by hypoxia and also seems to be reduced by increased activity of the respiratory muscles (11.4. 16. This additional ventilation. but the remaining ventilatory response to CO2 occurs much more slowly over minutes. However. For example. Acidosis in the arterial blood seems to increase ventilation at any given level of PCO2 while alkalosis has the reverse effect. on the right. The carotid body responds to changes in arterial PCO 2 and PO2 within a few seconds. PCO2 and 02 are expressed in mm Hg. It may be that the central chemoreceptors themselves are located at these superficial sites. 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. The ventilatory response to CO 2 is linear over a wide range of CO2 tensions (Fig. Severe acidosis seems to . 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). Ventilation lowers interstitial fluid pH by changing PCO 2 levels in the blood perfusing the brain. 27. With increasing hypercapnia the ventilatory response to hypoxia increases. 34). Neither the anatomic location nor how these receptors sense the CO 2 signal is known. In anesthetized and sleeping animals and humans there may be some threshold level of CO2 needed to initiate breathing (17. Cherniak and Guy S. Ventilatory responses to hypercapnia. and hypoxia. AV/APC02 increase. 23). With hypoxia. on the left. 2).398 Neil S. 28). However.=2O e '~'~'~e ". 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. and ventilation in liters per minute.30 _J ~ 10 \ c02 ~" ~ ~1 0 0 38 Arterial 42 Pco2 46 4O 3O I I I 80 120 160 P02 ~40 FIGURE 2. 16.

PCO 2 would rise by only 1 to 2 mm Hg each minute even if there were no breathing. 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).Chemical Control o f Respiration 399 also increase the slope of the ventilatory CO2 response line. the adequacy of ventilation and its time course is affected by how controller drive is distributed to different muscle groups. More importantly. as a consequence. THE CONTROLLED SYSTEM While the diaphragm seems to be the major muscle of inspiration. 34. Ventilation alters the gas stores of the body (the amount of CO2 contained in physical solution and chemical combination) and. 41). If all the body's capacity to store CO2 were immediately available. Hence. 19). particularly those that reduce chemical drive below usual levels. Dynamically the CO2 stores of the body behave as if they were contained in multiple compartments arranged in parallel and interconnected via the circulation. 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. blood and tissue levels of PCO2 and PO2 (13). CO2 exchange in tissues seems to be limited by perfusion. 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. On the other hand. 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. 7). 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. If breathing is stopped for one minute. 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. equilibration of CO 2 between the . 38). Hence. 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. large and abrupt changes in arterial PO2 are produced by ventilation changes. 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. 18. The time needed for signal transmission from neurons in the medulla and muscle contraction is very short and is in the order of milliseconds. In anesthetized animals. PaO2 will fall from about 100 to 40-50 mm Hg. may result in upper airway obstruction (6. Hence.

when muscle metabolism is increased and seems to increase the rapidity of ventilation changes (39). Since both speed of response and energy cost change with alterations in controller sensitivity. as they are in some patients with pulmonary disease. 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. However. Changes in the controller as well as in the stores affect the dynamics of ventilatory control. Longobardo blood and poorly perfused tissues may be extremely slow requiring hours. keep CSF acidity more constant than that of the arterial blood (1. increasing the rate of perfusion to muscles accelerates the change in arterial PCO2 during exercise. 30). 17. the less the circulation time and the faster the transfer of information. increasing controller gain or the PCO 2 set point accelerates the speed with which disturbances in blood gas tensions can be corrected (20).400 Nell S. . Also. This optimization may involve a "Figure of Merit" defined as the ratio of liters of CO2 expelled per liter 02 consumed in breathing (30). 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). as well as active and passive mechanisms which affect H+ exchange between the brain and the blood. the sensitivity of the controller may be optimized in these patients. 13). 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. increasing controller sensitivities has a decreasing effect on CO2 removal (9). 30). increasing controller sensitivity raises ventilation and the 02 cost of breathing. The higher the cardiac output. The speed with which peripheral and central chemoreceptors receive information of changes in PCO2 and PO2 at the lung depends on the cardiac output. increases in cerebral blood flow which occur with hypoxia and hypercapnia minimize changes in interstitial fluid acidity (1. When the O2 cost of breathing is high. But since the rate of CO2 elimination from the body is limited by perfusion. In general.4). On the other hand. Active buffering by the brain. 4). 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. 14. Likewise. 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. These energy considerations become very important when the 02 cost of breathing is very high. 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 .5 liter/min/mm Hg (Fig. the Figure o f Merit peaks at a controller sensitivity of 1. The dynamics of storage equilibration can affect the speed with which respiratory adjustments occur. 3). Cherniak and Guy S.

5 ~/3 ~ --"- 01 2 4 6 8 10 l t 2 i i 4 i -i--T'-'r---~--i 6 8 I0 Controller Sensitivity (L/min/mmHg) 3.5 3. INSTABILITIES IN RESPIRATORY CONTROL Control theory predicts that instability will occur in a system when controller gain is increased sufficiently. It is now recognized that similar waxing and waning of breathing can occur in sleeping individuals. .Chemical Control o[ Respira~on . (d) (lower right) when controllers receive central and peripheral chemoreceptor input as compared to when controllers receive peripheral chemoreceptor input only. .~.01V 3 (solid line).4 0 0 ._ 2. This is characterized by cyclic rises and falls in ventilation frequently accompanied by periods of apnea. 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. as shown in Fig. there are excessive delays in information transfer. 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. g Z + . ~ 6 8 10 2 4 6 8 10 Controller Sensitivity (L/min/mmHg) F I G U R E 3. O 1 0.51"-/""% ~ 101 _ _ . 4. who have no obvious nervous system disease or evidence of circulatory failure (9.0 .Or- 401 2~r C 1.0 O ~ 1. blood pressure and heart rate rise and fall with ventilation.0 0.. 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. [Data from Longobardo e t al. . ~ . (30)].0 "~ 2. (c) (upper right) when PaCO 2 = 80 mm Hg and cardiac output = 5 L/rain.Ol ~s 1. Ventilation increases . or system damping is too low (8). All graphs show values when energy costs are calculated by E = V3 (broken line) and E . 2 // I --~1.5 ~_2. (b) (lower left) when PaCe 2 = 40 mm Hg and cardiac output = 50 L/min. Frequently it is also associated with cyclic variations in other physiological systems. .5 I I I I l I I I I 2 4 ~'~. E .5 b v2+ ol i:Fd 0.. Instability can occur in the respiratory control system and produces Cheyne-Stokes breathing.I/2 + 0.e-*%.. For example. 27.

During sleep both threshold and resting PCO 2 are elevated and the ventilatory CO2 response line is shifted to the right. Record of periodic breathing in a sleeping human. Episodes of obstructive apnea. there is a threshold PCO 2 below which apnea occurs (8. 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. linearly as PCO2 is raised so that controller gain is unaffected by increasing hypercapnia. One idea of the genesis of obstructive apnea is as follows. Apnea during sleep has been classified as central. 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. 34). Hence arterial PCO2 will reach threshold valued more easily (20). air flow. 14). 25). Since the relation between hypoxia and ventilation is nearly hyperbolic. i. increases in controller gain occur continuously and at an increasingly greater rate as hypoxia becomes more severe. and lower trace. as shown in Fig. The elevation in threshold PCO 2 allows apnea to occur readily during sleep.402 Neil S. Breathing waxes and wanes but apnea is obstructive since there is no air flow even though rib cage movement continues. no air flow despite continued respiratory activity (9. 27. However in unconscious humans. 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. This threshold produces an alinearity in CO 2 control. absent respiratory activity.. as shown in Fig. rib cage displacement. Longobardo FLOW~ I I 20 seconds FIGURE 4. Cherniak and Guy S. may have a similar waxing and waning pattern of ventilation. The hypoxia that occurs during apneic periods is an important factor affecting stability. Upper trace.e. Because the amount of CO2 expired depends both on alveolar ventilation and alveolar PCO 2 (usually the same as arterial PCO2 ). 4. 34). Sleep diminishes the activity of upper airway . 5 (26. and obstructive. Obstructive apnea seems to occur as a result of upper airway occlusion during sleep. These tendencies toward instability are further aggravated if a slowing of circulation time occurs (9.

] muscles more than it decreases the activity of chest wall muscles (34. Based on the above . This is in fact the breathing pattern frequently reported in sleep apnea (27. As might be predicted from this view of the genesis of obstructive apnea. This would produce periods of both central and obstructive apnea during sleep. a similar cyclic fluctuation occurs in the activity of upper airway muscles. This disproportionate change in the relative activity of the two sets of muscles leads to upper airway obstruction. tracheostomy to relieve the upper airway obstruction does not prevent the occurrence of periods of central apnea (40). because it intensifies the hypoxia that occurs during apneic phase. Since some of the upper airway muscles seem to have a higher PCO2 threshold than the diaphragm. when obstructive apneas occurs is sometimes less regular than that observed during classic Cheyne-Stokes breathing. The obstructed period. it is likely that many apneas will be mixed in type. 38). (26). It would also explain why the ventilatory pattern. the two oscillations may not be exactly in phase (15). Another possibility is that obstructive apnea like central apnea is a manifestation of respiratory controller instability (9). Arousal terminates the period of obstruction by increasing once again upper airway muscle activity. Just as the activity of chest wall muscles waxes and wanes during Cheyne-Stokes breathing. Because the two sets of muscles differ in their responses to chemical stimulation.Chemical Control o f Respiration 403 20 O0 [] [] [] (L/min ) [] [] 10 [] [] 9 [] 9 [] [] [] [] oW I I 1 45 50 PCO (mm Hg) 2 55 FIGURE 5. 34). may increase the instability of breathing. Example of the shift in ventilatory response to CO2 occurring in quiet sleep [data from Gothe etal. 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.

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. 6 can also be produced by lengthening the circulation time. If at any time during breathing controller drive to the chest wall muscles exceeds that to the upper airway muscles. 6. 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. 19). or by decreasing the tonic activity of the upper airway muscles. a mathematical model which successfully simulates many of the apneic episodes during sleep has been proposed (15). The activity of both sets of muscles is considered to depend on peripheral and central chemoreceptors. At times obstructive apneas occur when chest wall muscle activity exceeds upper airway muscle activity. Note that the cycles are not precisely regular because of the interaction between chest wall and upper airway muscle activity in determining ventilation. 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. The exponent increasing the CO2 response of the upper airway muscles varies nonlinearly with hypoxia similar to that of the chest wall muscles. Cherniak and Guy S. as shown in Fig. Oscillations of the type shown in Fig. the controlled system consists of multiple body compartments interconnected by the circulation. 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. 12. 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). In the model. Because of the dissimilarities in the responses of the two sets of muscles to chemical stimuli.404 Neil S. the characteristics of the oscillations are not the same. A dead space is also included in the model. obstructive apnea is considered to occur. . These tests are extremely time consuming. These changes decrease the extent to which the controller curves need to be shifted to the right to produce the instability. The model contains a threshold level of PCO2 and PO 2 below which apnea occurs. The activity of chest wall and upper airway muscles is considered to vary sinusoidally during a breath. at other times there is little activity in either muscle set producing a central apnea. CO 2 and 0 2 drives are considered to multiply each other nonlinearly. The activity of the chest wall muscles increases linearly with hypercapnia and hyperbolically with hypoxia (19). Longobardo considerations.

This linearization is fortuitous and should not be taken to mean that changes in 02 saturation directly affect peripheral chemoreceptor output (19). Periodic breathing in sleep simulated by a mathematical modal. ! I !1j$. In addition. mm Hg . Time after onset of sleep is shown on the horizontal axis. shown by solid line. minutes i 7 i !:t~lHlyUi ~. ventilatory responses are measured at very high levels of PCO 2 far from those usually observed even in patients with disease. and a multicompartmant of the body gas stores. The curvilinear ventilatory response to hypoxia can be linearized by plotting ventilation against changes in arterial 02 saturation. 0 2 and CO2 effects on chest wall and upper airway muscles. . . Central apnees occur when chest wall activity falls to zero. I/:~1 ~ i . For example. Lowest panel. Using these tests patients are evaluated by determining the relationship between ventilation and changes in PCO 2 and PaO2.. changes in arterial blood gas tensions. and the activity of upper airway muscles like the tongue. Obstructive apnaa occurs when the activity of upper airway muscles is less than the activity of the diaphragm. During rebreathing tests. : :::I:AI:: i :! ! . ! I ~!/ II -~: : / / l / i ~ ! ! ! ! ::ii~. . Third panel.//ll!!il-[i~[][]i.t!V_Ll|!!!iil]ii!i!i!~ i Muscle Electrical Activity !ii 5 6 Time. changes in the electrical activity of chest wall muscles like the diaphragm. Behavioral and psychological effects have been shown to modify responses . These tests of chemosensitivity have been criticized on several grounds. liters FIGURE 6. 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. .!.2r J ' . shown by broken line. iiJi ~ "tJ L~ ]tll. A fuller description of the modal is given in (15). changes in tidal volume. inhalation of CO2 is an unnatural stimulus in the sense that it rarely if ever occurs except in laboratory situations. : ~ l : !1/|! '.~ ill = [ : : i : " ~/'d : . 8 Tidal Volume. L E~ . The model includes central and peripheral chemoreceptors.Chemical Control of Respiration 405 Blood Gas Tensions. Upper t w o panels.:.

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