Eur Respir J REVIEW 1988, 1, 651~60.

Studying the control of in man

H. Folgering

Studying the control of breathing in man. H. Folgering. Dept of Pulmonology, University of Nijmegen, ABSTRACT: The control system of breathing can be considered as a closed­ Medisch Centrum Dekkcrswald, The Netherlands. loop system, consisting of two subsystems: the controlling system and the controlled system. Both subsystems are defined by their input-output Correspondence: Dr H. Folgering, Dept of Pul­ relationships. In the controlling system the input is the blood gas value; the monology, University of Nijmegen, Medisch Centrum Dekkerswald, Postbus 9001, NL-6560 GB output is some parameter of ventilation. The controlled system is charac­ Groesbcek, The Netherlands. terized by an input of ventilation, and an output of blood gas values. In the closed-loop situation the control of breathing can be influenced by outside Keywords: Control of breathing; C02-response "disturbances", threatening to disrupt the regulation of the constancy of curves; 0 -response curves; respiratory centres; 2 the internal environment. When studying the control of breathing, and man. therefore studying the strengths or defects of this homeostatic system, one has to decide whether one intends to investigate the closed-loop or the Received: December 27, 1987; accepted after open-loop situation, and which defect in a subsystem may be the cause of revision April 22, 1988. a disrupted bomeostasis. What non-feedback stimuli may be active at the moment of the Investigation? How can they be kept constant or elimi­ nated? What possible effects from drugs, beverages, nutrients (possibly consumed hours earlier) may still be present? In particular, the output parameters of the controlling system should be carefully chosen to repre­ sent that part of the system that one intends to Investigate. Disruptions of the control of breathing may have serious consequences for several cate­ gories of patients, e.g. those with chronic obstructive pulmonary disease (COPD), asthma, sleep apnoea, sudden Infant death syndrome, several neurological syndromes, and the hyperventilation syndrome. Adequate investigation of the control of breathing In these patients is of great impor­ tance for their treatment. Eur Respir J., 1988, 1, 651-660.

In the nonnal resting and awake human the level of tory effects of, e.g., C02 means that all other stimuli ventilation is~ driven by two major stimuli. The most have to be kept constant or changed in a quantifiable important is the C02-stimulus which functions in the way. . homeostatic control system of the body for pH/Pco2 The control system for C02 has a feedback loop. The second important drive is a non-feedback drive, from neuronal Chemical control of breathing structures that mediate wakefulness or the level of arousal. Furthermore body temperature, certain hormones, open A block diagram of the feedback loops in the chemical or closed eyes, any motor activity, listening to music, control of breathing is shown in figure 1. adrenal-sympathetic tone, the degree of filling of the takes place in the , resulting in certain levels of Po2 urinary bladder, recently imbibed beverages such as coffee and Pco~ and a certain pH in the arterial blood. The or alcohol, and the type of nutrition all contribute to the periphcnil chemorecepLOrs sense t.hc blood gas levels and level of resting ventilation and consequently have to be convert them into neuronal signals which are transmiucd controlled when studying the regulation of ventilation. to the brainstem neuronal respiratory centre. The pH/

There are two major groups of ventilatory stimuli: feed­ Pco2 of the mosr vulnerable of all tissues, back stimuli and non-feedback stimuli. The former are the central nervous system, is sensed by the central ) the chemical stimuli: pH, tension (Pco2 at the ventral medullary surface. Affer­ ) and oxygen tension (Po2 of the arterial blood or intersti­ ent signals from both chemoreceptors are processed in tial fluid, that are detected by chemoreceptors, and are the ponto-medullary neuronal respiratory centre. The altered by the level of ventilation. The latter are hormo­ output of this centre is transmitted to the motor neurones nal or neuronal stimuli, the intensity of which is not of the respiratory muscles at the appropriate spinal affected by the level of ventilation. Both types of stirrmli levels. The activity of these muscles changes the con­ may interact with the other, so that studying the ventila- figuration of the thorax, and consequently changes the 652 H. FOLGcRING

•centersM

PoO

PoC02 (pHo)

Fig. I. - Block diagram of the ventilatory control system. bid: blood; CSF: ccrebro spinal fluid; cemr chemo: central chemoreceplors; perif chemo: peripheral chemorcceptors; centres: "respiratory centres" in pons and brainstem; RM motoneur: spinal motor neurones of the inspiratory muscles; IC: intercostal inspir.ttory muscles; Dia: diaphragm; Ppleura: pleural pressure; Elast: elastic properties of the parenchyma; Palv: alveolar pressure; Raw: ; VDan: anatomical !ieadspace; VDphys: . physiological deadspace; hypothal: hypothalamus; som+visc aff: : : somatic and visceral afferents; cortex: forebrain cortex; YE: total ventilation; VA: alveolar ventilation Pao2 arterial oxygen tension; J>aco2 arterial carbon dioxide tension; pHa: arterial pH.

pleural pressure. These pleural pressure swings, after ventilation, and as the output the arterial (interstitial) pH modification by the elastic properties of the parenchyma or arterial blood gas values. The input-output relation­ of the lungs, cause alterations of pressure in the alveoli. ships determine the gains in these subsystems. Depending on the flow resistance in the airways, more or Analogous to technical control systems, some of the less air is moved in or out of the lungs. The net gas properties of the ventilatory control system are being exchange in the alveoli is detennined by the relative described by some authors in terms of a "set-point": a deadspace ventilation, by the dilution of the "fresh" air certain blood gas value that should be maintained. A in the residual volume, by the diffusion process over the set-point in technical control systems is a signal that is alveolar-capillary membrane, and by the ventilation­ absolutely constant, and independent of changes in the ratio. environment. The measured value of the controlled Basically the properties of this chemical control loop parameter in these technical control systems is compared can be studied in two ways: 1) the ventilatory control to this reference signal. When there is a difference be­ loop (as shown in fig. 1) can be kept functionally intact. tween both signals, the control system is activated and

Its ability to maintain homeostasis for Po2 and pH/Pco2 the difference between the controlled parameter and the in the presence of external disturbances can be tested. reference value is minimized. If such a set-point mecha­ This type of study is carried out, e.g., when blood gas nism were present in the ventilatory controlling system, levels are measured in humans after administration of this would presuppose a {presumably neuronal) compara­ drugs, when exercising, during sleep, or under psycho­ tor system, where the afferent signals are logical influences such as hypnosis or mental stress; 2) compared to some constant signal representing a desir­ the ventilatory control loop can be opened, and arterial­ able blood gas level. There is no neurophysiological

or end-tidal-Po2 or Pco2 can be kept at desired levels so evidence for the existence of such set-points in the control that ventilation does not influence blood gas values, as is of breathing [1).

done when making C02 or 0 2 response curves; or the An alternative approach in describing the function of blood gas levels do not influence ventilation as in paraly­ the control system is based on the view that, in the closed­ sed subjects who are artificially ventilated. loop situation, the controlling and the controlled systems In both open- and closed-loop studies, subsystems of have to be in equilibrium: the output of the controlling the control system can be studied. These subsystems are system is the input of the controlled system and vice then defined and characterized by their input-output versa. Thus the intact control system has to include the relationships. The two major subsystems of the ventila­ characteristics of both the controlled system (metabolic - - tory control system are the "controlling" and the hyperbolae) and of the controlling system (C02 and 0 2 "controlled" system. The controlling system is defined response curves). When plotting these input-output rela­ as the subsystem with an input of a blood gas value; and tionships of both subsystems, the result is that the total the output is a ventilatory parameter such as minute control system settles in the crossing of both lines. This ventilation, pleural pressure, respiratory muscle electro­ is called the "working point" (fig. 2). Changes in the myograph (EMG), mouth pressure, etc. The controlled ventilatory response curves or in the metabolic hyperbo­ system is defined as having as the input (alveolar) lae change the position of this working point. STUDYING THE CONTROL OF BREATHING IN MAN 653

point remains at the resting Pco2 level. Only at higher CONTROLLING submaximal exercise levels in normals, is there an in­ crease in ventilation which is disproportionate to the

increase in metabolism (C02 production), resulting in a disruption of the normal ventilatory control and in a • lowered Pco2 The exercise level at which the ventilation increases more than the C02 production, resulting in hypocapnia, is sometimes used to determine the "anaero­ bic threshold". This is misleading; there is substantial evidence that this relative hyperventilation is not a res­ piratory compensation of a metabolic acidosis, caused by the anaerobic metabolism and lactate production. Patients with "McArdle's disease" cannot make lactate, but do show such a relative hyperventilation and hypocapnia CONTROLLED [12). Furthermore, if lactacidosis is pre-existent before the exercise test, at a certain exercise level there is still a disproportionate increase in ventilation, resulting in hypocapnia and respiratory alkalosis [13]. PA C02 Sensory input from proprioceptors can profoundly affect the control of breathing. In particular, afferent signals Fig. 2. - Characteristics of the controlling, and of the controlled subsystem in the ventilatory control system. The characteristics of the from spindles in the intercostal muscles have potent effects controlling system arc described by the CO -response curve: the input in this respect [14-17). These effects have to be taken

par~e~er is. alveolar (arterial) Pco2 (PAco:); the output parameter is into accoum when studying control in loaded breathing, ventilauon (y). The controlled system is characterized by the meta­ e.g. in chronic obstructive pulmonary disease (COPD) bolic hyperbola: input ventilation, output alveolar Pco . 1n tbe closed­ patients, or in pharmacological studies with drugs that loop situation, the control system has to settle in the Point where the input of the controlling system equals the output of the controlled depress the activity of the gamma-motor neurone system system, and vice-versa. This crossing point of both characteristics is in the intercostal muscles [18). called the working point of the control system. A rather unsuspected source of disturbances of venti­ latory control in the closed-loop situation is the ftlling state of the urinary bladder: distension of the bladder Closed-loop studies causes a decrease in the amplitude and frequency of breathing [19]. In the closed-loop situation of the chemical control system, the basic question is "how adequate is the chemi­ cal control loop in maintaining homeostasis for Po and The controlled system

Pco2, in spite of a disturbance from outside this c~ntrol system?" This "disturbance", is often a change in a The controlled system is defined as having an input of non-feedback drive, or the application of a certain drug. ventilation, and an output of arterial blood gas values. In Consequently, the parameters that are studied in such anaesthesia and in intensive care medicine with patients investigations are the blood gas levels of Pco and Po or on respirators, working with the characteristics of this arterial pH. Drugs that have been investigatid in such a controlled system is part of daily practice. The graphic way include: alcohol, caffeine, sedatives, hormones representation of this input-output relationship for CO is (progesterones, adrenaline, thyroxine), endorphins, res­ called the "metabolic hyperbola". The position of this piratory stimulants such as doxapram and almitrine, hyperbola is determined by C02 production and thus by opiates and their antagonists, etc. [2-7). metabolism. ll is, therefore, not surprising that the The effects of wakefulness and sleep are often studied characteristics of this controlled system are altered by in the closed-loop situation. Even when awake, open or substantial changes in nutrients [20, 21]. Furthermore, in situations like haemodialysis, C0 is closed eyes make a difference in arterial Pco2 [8). Slow 2 wave sleep generally depresses ventilation, whereas rapid eliminated from the body via the dialysis bath [22, 23]; eye movement (REM) sleep is eucapnic or even hy­ since the arterial Pco2 remains normal, the characteristics pocapnic [9). Mental stress tests cause respiratory of the controlling system have to change also. alkalosis [10). The transfer function from ventilation to blood gas In open-loop studies more or less adequate attempts values is· affected by the mechanical properties of the are being made to keep these non-feedback factors lungs and airways: airway resistance (asthma, COPD), constant by making the subjects read, watch a neutral compliance of the lungs (pneumonia, adult respiratory television programme, or listen to quiet music [11]. distress syndrome (ARDS)) and compliance of the thorax Exercise is a potent non-feedback ventilatory stimulus. (scoliosis, thoracic trauma). The mechanism of this stimulus has been studied inten­ sively, but has not yet been elucidated. During light to The controlling system moderate exercise the arterial blood gas levels remain constant. Both the metabolic hyperbola and the CO - The controlling system is defined as having an input of response curve change in such a way that the working arterial blood gas values, and a ventilatory parameter as 654 H.FOLGERING

output. The graphic representation of the input-output situations where the oxygen dissociation curve is sub­

relationship is called a ventilatory response curve to C02 stantially shifted [26]. • or to 0 2 Depending on the degree of invasiveness with The C02 control loop has two sensors that detect the which the experimenter and the subject'> are prepared to input stimulus: the peripheral and central chemorecep­ comply, the real input to the chemoreceptors can be tors. The former sense arterial PcojpH. There is good measured in indirect or more direct ways. The same is evidence that the receptor mechanism measures arterial true for the output parameters of this controlling system. pH changes, irrespective of whether they are brought ) In extreme invasiveness this means that arterial Po2 and about via respiratory (C02 or metabolic ("fixed acid") Pco2 and pH of (CSF-pH ) are mechanisms [27]. In normal subjects end-tidal Pco2 is a ; measured directly or, on the other hand, minimal inva­ good representation of arterial Pco2 this end-tidal Pco2 siveness is approached when end-tidal partial pressures value can be measured with any fast-responding device are measured and thought to be representative of the real such as a capnograph or a mass spectrometer. The stimu­ stimuli. Output parameters can be measured in even more lus for the central chemoreceptors is more complex and ways, ranging from electroneurograms of phrenic or can hardly be measured directly. There is a transfer factor intercostal nerves, EMG's of the corresponding muscles, from the extracellular PcojpH in the interstitial fluid , to plethysmography of thoracic and around the central chemoreceptors to the arterial blood. abdominal displacements. It is clear that a description of Cerebral blood flow and active ion transport across the the controlling system is completely dependent on the blood-brain barrier play an important role in this trans­ input and output parameters actually measured. They have fer. There also seem to be independent pH and Pco2 to be stated clearly, and conclusions from the studies effects on these chemoreceptors [28). have to be restricted with regard to the way the system The closest one can get to this actual stimulus is is investigated. For instance, in COPD patients the end­ sampling cerebrospinal fluid (CSF) by suboccipital tidal partial pressures of 0 2 and C02 are often not puncture [29] or by lumbar puncture [30). When auempt­ representative of the arterial values, and the ventilation ing to measure these stimuli as directly as possible, one is not a good measure of the output from the respiratory also has to be as invasive as possible. In these condi­ centres [24]. The problems concerning measurement of tions, one of the basic physical laws should not be for­ the various ventilatory output parameters in COPD pa­ gotten: any measurement on a system influences the tients were shown by ScANO et al. [25]. who compared system. In the case of invasive measurement of blood ), diaphragmatic EMG, mouth occlusion pressure (P0 and gas or CSF values the subjects will either hyperventilate mean inspiratory flow (Vr{fr). They found very different or hold their breath during the procedure and, therefore, responses to changes in end-tidal C02 with these three change their PcojpH values. output parameters. Methods have been developed to separate the central and peripheral chemoreceptor effects by using the dif­ ferent temporal responses of the two chemoreceptor

Input parameters for the controlling system systems to step changes in end-tidal Pco2 (dynamic end-tidal forcing (DEF)-technique). The ensuing ventila­ tory change can be separated into a fast and a slow For the 0 2 control loop the input parameter that is actually sensed by the arterial chemoreceptors is the component. The time constants and the gains from these . two components can be derived mathematically [31]. The arterial Po2 In experimental conditions this parameter can be measured directly by arterial blood sampling, or final evidence that these fast and slow responses could by an indwelling Po -elcctrode. If it is desirable to be really be attributed to peripheral and central chemo­ 2 receptor responses, respectively, was discovered in less invasive, the arterial Po2 can be approximated by the end-tidal value. However, one has to bear in mind that animal experiments with separate perfusion of carotid even in normal subjects there can be an arterial-alveolar and vertebral arteries [32]. Using the DEF-technique Po gradient of up to 1.5 kPa. This gradient changes as requires computerized shaping of the inspiratory Pco2 2 profile, plus computer analysis and curve fitting of the ventilation changes. Alveolar Po2 measurement requires a fast 0 -analyser with a response time of about 0.1 s. ventilatory response. In normoxia, the peripheral chemo­ 2 receptor control loop for Pco contributes 34% to the Transcutaneous Po2-electrodes are useful for trend 2 monitoring, but not for measurements of an input total gain in the C02 control loop [31]. In hypoxic - - parameter in ventilatory control studies. The oxygen conditions there is an interaction between 0 2 and C02 saturation (Sao ) measured with a pulse-oximeter can stimuli in the peripheral chemoreceptors: 2 increases the C0 -sensitivity, and increases well be used as an input parameter. The shapes of the 2 oxygen-response curve and of the haemoglobin oxygen the hypoxic sensitivity. dissociation curve fortuitously make rectilinear ventila­ tion-Sao2 relationships that can be described by very simple mathematical equations. However, one must bear Output parameters of the controlling system in mind that the stimulus for the chemorcceptors is Po2 • and not Sao2 Measurement of Sao2 a'> input stimulus The output of the ponto-medullary respiratory neuronal may be wrong in situations of carbon monoxide intoxi­ centre consists of the neuronal signals travelling in the cation, in the presence of a substantial amount of spinal cord to the motor neurones of the respiratory abnormal haemoglobins, in very severe anaemia, and in muscles. Also descending signals from the corticospinal STUDYING THE CONTROL OF BREATHING IN MAN 655

tract, mediating volitional respiratory commands, project measure volume displacements. Use of magnetometers to these motor neurones. Both groups of signals travel in gives a measurement of linear displacement. Magnetome­ separate tracts that can be lesioned independently and ters in both anterior-posterior and in lateral direction give can give rise to different clinical syndromes with a a beller approximation of volume. However, most mag­ dysregulation of breathing (33]. netometers measure displacements vs a fixed-point, and The output from the spinal motor neurones of the res­ consequently are subject to movement artifacts. piratory muscles to the muscles themselves travels in The application of coils around the thorax and abdo­ peripheral nerves such as the phrenic nerve and intercos­ men measures changes in the volume of the cylinder that tal nerves. In contrast to the widely used quantification is surrounded by the coils. This respiratory inductive of this neuronal output in animal experiments, these output plethysmographic (RIP) signal can be used satisfactorily parameters have not yet been used in humans. as an output parameter, provided that rather complex The next station in the output from the controlling calibration procedures have been applied, and that the system, the electrical activity of the respiratory muscles subject absolutely does not change position after the has, however, been used successfully by many investiga­ calibration procedure. It is claimed that RIP can tors. Electromyographic activity of the respiratory muscles measure diaphragmatic and intercostal contributions to can be recorded with needle- or wire-electrodes (e.g. in the respiratory (38]. This presupposes that the parasternal intercostal muscles), electrodes on an oeso­ all thoracic cage movement is made by the intercostal phageal balloon (diaphragm), or surface electrodes muscles, and that abdominal wall displacements are only (intercostals, diaphragm, and accessory muscles). Usu­ a result of diaphragmatic contractions. These supposi­ ally EMG-activity is rectified and integrated. When per­ tions cannot be maintained in view of recent insights of formed correctly, these recorded and quantified EMG's mechanical effects of respiratory muscles [36]. The RIP can be used as output parameters of the respiratory signal is, therefore, very useful in non-invasive qualita­ controlling system (34]. tive or semi-quantitative assessment of ventilation and The contraction of the inspiratory muscles causes pres­ thoracic and abdominal movements. Ambulatory moni­ sure changes in the pleural space. These pressure changes toring of breathing, or monitoring during sleep, can be are a result of the combined activity of all respiratory performed with RlP, keeping in mind that only semi­ muscles. They can be measured with an oesophageal quantitative (increase/decrease) assessment of breathing balloon. This output parameter of the controlling system can be carried out. can be modified by the compliance of the lungs and the Ventilation measured at the mouth and nose is the final thoracic wall. Measurement of oesophageal pressure output parameter of the controlling system. The way in swings can be very useful when airway obstruction makes which the subject is connected to any apparatus influ­ the measurement of ventilation an unreliable output ences the measurement. A face-mask over mouth and parameter, as in COPD or obstructive sleep-apnoea or nose increases tidal volume, and lowers respiratory fre­ hypopnoea. The transdiaphragmatic pressure only gives quency, as compared to a mouthpiece and noseclip [39, an indication of the contribution of the diaphragm to the 40]. Volume displacement can be measured as volume pleural pressure swings. Interpretation of the measure­ (spirometer) or as integrated flow (pneumotachograph). ments of oesophageal vs transdiaphragmatic pressure is Both types of measurement are useful in specialized complex [35, 36]. situations, depending on the required frequency response, The pleural pressure swings are transmitted to the resistance and inertia in the system, open or closed alveoli, the transfer factor being the elastic properties of breathing systems, etc. [41]. the parenchyma of the lung. Measurement of alveolar pressure can also be used as an output parameter. Subsystems within the controlling system Occluding the airway for a very short time (0.1 s) makes the pressure in the mouth equilibrate with the alveolar Using two or more of the measurements described pressure. Thus, it is possible to measure mouth pressure above, it is possible to describe the transfer factors in (P ) as being representative of alveolar pressure when 0 various subsystems in the output system of the control­ there is no airflow during the occlusion (37]. ling system. Comparing quantified EMG-activity and This type of measurement presupposes that 0.1 s is a oesophageal (or transdiaphragmatic) pressure gives an short enough time for load compensating reflexes not to impression of the electromechanical coupling in the come imo effect, and long enough for equilibration of inspiratory muscles [42]. This transfer factor changes in alveolar and mouth pressures. This is certainly true in muscle weakness, fatigue, and change of position on the normal subjects; in COPD patients this may not quite be length-tension diagram of the muscle. the case but the P .~ output parameter in these patients is 0 The EMG-ventilation relationship is another parameter always a closer approximation of the respiratory centre to quantify electromechanical coupling. This relationship activity than is the output measured from minute venti­ is also affected by the resistance in the airways. . lation. Furthermore, the P0 1 is a reliable output parame­ ter only if the neuromuscular system is not diseased, weakened, or fatigued. col-response curves One of the least invasive output measurements is the quantification of respiratory movements of the thorax One of the methods most widely used to test the proper­ and of the abdomen. The aim of these methods is to lies of the controlling system in the open-loop situation 656 H.POLGERING

is to construct the C02-response curve. The relationship [54-55]. In spite of the fact that resting ventilation in the between alveolar (arterial) Pco2 and minute ventilation sitting position is higher than in the supine position, the to is determined by the functioning of the chemoreceptors, ventilatory response to C02 seems be unaffected by the brain stem neuronal respiratory centre, the descend­ posture [56]. In chronically hypercapnic patients the

ing neuronal pathways, the respiratory muscles, and ventilatory response to C02 increased after a carbohy­ by the mechanical properties of lungs and airways. drate meal that raised the respiratory exchange ratio [21). Furthermore, it is assumed that all non-feedback inputs Obstructive pulmonary disease, especially of the blue and

to the controlling system are in standard conditions. bloating type is accompanied by low C02-sensitivity [24, Considering this multitude of factors affecting the Pco2 57). ventilation relationship, it is not surprising that there is a Vibration of the thoracic wall increases C02-sensitiv­ huge range of normal values: from 3- 33 l·min·1··kPa·1 ity considerably [16]. A 5 min period of hypoxia

[26, 41]. It is, therefore, very difficult to distinguish increases the C02-sensitivity for 40 min [58]. Increased between normal and pathological ventilatory responses body temperature gives a higher slope [59]. Increased to C0 • Perhaps the only criterion in this respect should gravity only shifts the C0 response curve to lower Pco 2 2 2 be: a response or not. There are three basic methods for levels, with no significant change in slope [60]. Daily

determining C02-sensitivity: the steady-state method, the successive C02 response curves seem to increase the slope rebreathing method, and the dynamic end-tidal forcing [61]. Hypnosis decreases C02-sensistivity [62]. Person­ technique. In the steady-state method the alveolar (arte­ ality, familial, racial and genetic influences have also

rial) Pco2 is elevated for a sufficient time to obtain a been described [63]. steady ventilatory response. The time constant depends on the equilibration rate of the extracellular fluid compartment around the central chemoreceptors, on the Hypoxic response curves , adaptation of cerebral blood flow to the changed Pco2 and on the time constant of the neuronal circuitry in the In hypoxic ventilatory responses the time constant of brainstem. The time to reach a steady-state ventilation in the ventilatory response is relatively short: about 18 s hypercapnia ranges, according to various authors, from 5 [26]. Therefore, no distinction is generally made between min [31] to 20-25 min [1]. This is the classical "Oxford" steady-state and non-steady-state responses. As previously method [43]. mentioned, the actual stimulus for the peripheral chemore­ . In the rebreathing method, as described by READ [44]. ceptors is the arterial Po1 If this parameter is used in the description of the 0 -controller, the adequate equation is the subject rebreathes a mixture of 7% C02 in oxygen. 2 Various authors have modified this method by using of a hyperbola:

breathing of gas mixtures with or without C02 in the starting condition. Both steady-state and rebrealhing methods yield the same slopes, the latter curves being In this equation Vo is the horizontal asymptote; C is shifted to the right, i.e. higher Pco2 levels. the vertical asymptote; and A is the shape parameter. In the DEF-technique the inspiratory Pco2 is changed abruptly; the ventilatory response is analysed by com­ The normal values of A range from 40-280, and C has puter models based on a two compartment model for the value of 32 [26] (note that these values are based on

central and peripheral chemoreceptor loops. This method Po2 values in mmHg). When the Sao2 is used as an input has been validated in animal studies [32]. Also, in carotid stimulus, the ventilatory response can be described by a body resected subjects this method yields only one slow, linear equation with a negative slope. The normal range cenlral component [31]. of this slope is 0.16-1.76 l·min·1·% desaturalion·1 [41). When breathing hypoxic mixtures, the subjects hyper­ The shape of the C02-response curve has been the • subject of discussions. The classical Oxford approach is ventilate and blow off C02 Due to the interaction - description by means of a straight line. Undoubtedly this between the 0 2 and C02 stimuli, this leads to a decreased is mathematically the simplest description. However, in hypoxic response. Therefore, it is necessary to maintain

their review in 1986, CUNl\'INGHAM et al. [43] discussed a constant arterial Pco2 level during a hypoxic response, the problems of ventilation around l11e normal value of by adding an adequate amount of C02 to the inspiratory , air. Pco2 and considered the possibility of a so called "dog­ leg" in normoxia. FoLGERING et al. [45] found curvilinear Another source of error in the hypoxic response is the C02 responses which can be described by an exponential fact that the hypoxic depression of the central nervous equation or by two straight lines. In the lower ranges of system counteracts the stimulatory effect of the periph­ eral chemoreceptors. This leads to a biphasic response: C01-responses in particular, interactions can occur be­ tween the C02 stimulus and the exercise stimulus [46) or the initial increase in ventilation from the chemoreceptor stimuli from hypothaJamic centres [47-49]. stimulation is somewhat diminished later by the central hypoxic depression. Other theories about this biphasic The ventilatory C01-sensitivity is affected by hormones, drugs, alcohol, endorphins [2-5], is reduced at older ages hypoxic response include adaptation of the peripheral [50- 52), seems to be lower in females than in males, and chemoreceptor and increases in cerebral blood flow due changes during the menstrual cycle [6, 53]. The effect of to the hypoxia. athletic training is equivocal; reduced as well as aug­ Hypoxia is a potentially dangerous condition. Record­ ing of hypoxic response curves should be carried out mented C02-responses in athletes have been described STUDYING THE CONTROL OF BREATHING IN MAN 657

with constant monitoring of the subject and his arterial controlling systems arc affected:

Po2 or Sao2 (transcutaneous Po2 monitoring is insuffi­ impedes a normal gas exchange in the controlled system. cient and too slow in this situation) and preferably also On the other hand, stimulation of irritant receptors in the with ECG-monitoring. A clinician should be present. airways stimulates ventilation and makes the asthmatic hyperventilate in the early stages of an attack. In the past, the carotid bodies of some of these patients have CHnical applications been denervated in order to diminish the sensations of dyspnoea. The result'> did not warrant a widespread use In several clinical situations the control of breathing of this procedure. These chemodcnervated patients did is disrupted. In more severe COPD patients, in respira­ not have a hypoxic response any more [31], nor did they tory muscle dysfunction, and in pharmacological sup­ react to drugs like doxapram or almitrinc. Some arterio­ pression of the chemoreflexes, one finds hypoventilation sclerotic patients have been chemodenervated acciden­ and respiratory acidosis. On the other hand, a respiratory tally during carotid endarterectomy. alkalosis occurs in conditions such as pneumonia, The COPD patients can be subdivided into two groups: pneumothorax, pulmonary embolism, heart failure, early those who maintain their PcoJpH homeostasis, and those acute asthma, interstitial lung diseases, and in several who do not. They are also called "pink puffers" and neurological conditions. Oscillations in the system with "blue bloaters" or "fighters" and "quitters", respectively. alternating hypercapnic and hypocapnic periods can be In these patients, it is not clear what properties of the seen in Cheyne-Stokes breathing, when either the con­ controlling or of the controlled system makes one patient troller gain is changed grossly (as in terminal patients), eucapnic, and another hypercapnic. There are indications

or when there are time-lags in the control system (very that the C02-responses in the eucapnic group are steeper low cardiac outputs). Increasing the cardiac output or the than in the hypercapnic group [14]. There are also

C02-stimulus eliminates this pathological breathing indications that the 0 2-sensitivity is a familial trait that pattern. may determine C02 retention [57]. The theory that C02 Various drugs affect ventilatory control. Anaesthetics, retention in some COPD patients is a result of the high­ sedatives, alcohol and certain analgesics depress the frequency breathing pattern, as proposed by SoRu et al. controller gain resulting in a ventilatory insufficiency and [68], should be re-evaluated. Their hypercapnic patients hypercapnia. They depress the wakefulness drive, or the were on diuretics. Many diuretics cause a metabolic activity in the medullary neuronal respiralOry centre. Most alkalosis and, therefore, eliminate part of the chemical of them do not seem to affect the chemoreceptor activity ventilatory drive. in animal experiments. Caffeine, almitrine, doxapram, During sleep when the wakefulness drive is dimin­ progesterone, adenosine, adrenaline and high doses of ished the hypoventilation may be of such an extent that salicylate increase the gain in the controlling system. some COPD patients become hypoxic. Obesity and Some of them act specifically on the peripheral chemore­ hypertension increase the risk of nocturnal hypoxia. Sleep ceptors. studies with polysomnography of respiratory parameters Theophylline has a special place since it has its stimu­ and arterial are indicated in these latory effects on both the controlling system and the patients. In a group of COPD patients there is a fair

conductivity of the airways in the controlled system. The correlation between daytime arterial Po2 and sleep possible effect of theophylline on respiratory muscles is desaturations [9]. In the experience of this author the not yet clear. · daytime oxygen saturation in the individual patient is

In situations where the C02 production is increased, insufficiently predictive for the frequency and depth of such as exercise, carbohydrate alimentation and intraperi­ nightly desaturations.

toneal C02 loading [64], the gain in the controller is Neurological syndromes such as cerebral tumours, increased. When the C02 production seems to be reduced, cerebrovascular accidents, Shy-Drager syndrome, Locked­ in syndrome, give rise to dysregulation of ventilation, e.g. in haemodialysis where C02 is removed in the dialysate, the controller gain is also reduced [22, 65]. either awake or asleep. Descending pathways from the These patients become slightly hypoxic. It is not yet clear corticospinal tract or from the reticulospinal tracts can be how this C02-flux is perceived by the organism, and severed separately by accidents, or iatrogenically by how it affects the control mechanisms. Respiratory neurosurgical interventions. Corticospinal tract lesions oscillations in blood gas values may be the cause. Further make voluntary breathing movements impossible, and research in this field is certainly needed. reticulospinal tract lesions make automatic breathing In neonates and babies under one year, there is a risk impossible: breathing has to be performed consciously, of sudden infant death syndrome (SIDS). There are and stops during sleep [33). indications that defects in the controlling system of breath­ Psychological stress, high sympathetic-adrenergic tone ing during sleep may play a role in this affliction. and possible high activity in hypothalamic emotional centres all contribute to the hyperventilation syndrome. Constructing C02-response curves in sleeping near-miss SIDS children will identify high risk children by the In this syndrome the normal control of breathing is - absence of a response [66, 67]. It can be speculated that abandoned by the individual. The normal negative C02 older patients with "Pickwick's syndrome" could be feedback is often inverted into a positive feedback. When survivors of near-miss SIDS. such a patient is hypocapnic, adding C02 to the inspira­ In asthmatic patients both the controlled and the tory air, as occurs when rebreathing into a plastic bag, 658 H .FOLGERING

diminishes ventilation in about 40% of cases. This in­ 11. Haas F, Distenfeld S, Axen K. - Effects of perceived mus­ ical rhythm on respiratory pauem. J Appl Physiol, 1986, 61, creases the arterial Pco2 even more, until the Pco2 values have reached a normocapnic level. When for some reason 1185-1191. the ventilation in the hyperventilation patient is increased, 12. Hagberg J, Coylc E. Miller J, Carroll J, Martin W. - it remains high for a considerable time after the stimulus Exercise hyperventilation in patients with McArdle disease. J Appl Physiol: Respirat Environ Exercise Physiol, 1982, 52, is taken away. This "flywheel phenomenon" has also 991-994. been described in animal experiments [69, 70], and in a 13. Farrell SW, Ivy JL. - Lactate acidosis and the increase in mild form in normal human subjects [71). The hyperven­ VENo2 during incremental exercise. J Appl Physiol, 1987, 62, tilation and the ensuing respiratory alkalosis can cause a 1551-1555. cerebral vasoconstriction so that the oxygen supply to 14. Altose MD, McCauley WC, Kelsen SC, Chemiack NS. - the brain is temporarily impaired and the patient faints. Effects of hypercapnia and inspiratory flow resistive loading The dysregulation of ventilation in the hyperventilation on respiratory activity in chronic all-ways obstruction. J Clin syndrome might not give rise to grave clinical condi­ Invest, 1977, 59, 500-507. tions, but it occurs in many patients (about 10% of all 15. Altose M, Castele RJ, Connors AF, Dirnarco AF. - Effects patients seeking medical help [72)), is sometimes diffi­ of volume and frequency of on respira­ tory activity in humans. Respir Physiol, 1986, 66, 171- 180. cult to diagnose [73), and can be very disabling for the 16. Hida W, Susuki R, Kikuchi Y, Shindo C, Chonan T, individual. Sasaki H, Takishima T. - Effect of local vibration on ventila­ tory response to hypercapnia in normal subjects. Clin Respir Physiol, 1987, 23, 227- 232. Conclusions 17. Homma I. - Proprioceptive inputs from chest walls and their effects on respiratory sensations. In: Psychophysiology of When studying the control of breathing, one has to breathing. C.v. Euler and M. Katz-Salomon eds, Wenner Gren decide whether one wants to investigate the closed-loop Symposium, McMillan Press, Basingstoke, England, 1988, (in or the open-loop situation, and which non-feedback press). stimuli may be active at the moment of the investigation. 18. Folgcring H1bM, Smolders FDJ, Bemards JA.- The role of the (usirnotor system with respect to the contribution of the How can they be kept constant or eliminated? What diaphragm and the intercostal muscles to the respiratory tidal possible effects from drugs, beverages or nutrients pos­ volume. Pjluegers Arch, 1976, 366, 107-114. sibly taken hours earlier, may still be present? The output 19. Schondorf R, Polosa C. - Effects of urinary bladder parameters of the controlling system in particular must afferents on . J Appl Physiol: Respirat Environ Ex­ be carefully chosen to represent that part of the system ercise Physiol, 1980, 48, 826-832. that one intends to investigate. 20. Askanasi J, Rosenbaum SH, Hyman Al, Silverberg PA, Milic-Emili J, Kinney JM. - Respiratory changes induced by the large glucose loads of total parenteral nutrition. JAm Med References Assoc, 1980, 243, 1444-1447. 21. Rochester DF, Esau SA. - Malnutrition and the respi­ 1. Saunders KB. -In: Clinical physiology of the lung. Black­ ratory system. Chest, 1984, 85, 411-415. well Scientific Publications, Oxford, 1977. 22. Dolan MJ, Whipp BJ, Davidson WO, Weitzman RE, 2. Boselt GO. Kleine P, Fabel H. - Alkohol und atemregula­ Wassermann K. - Hypopnca associated with acetate hemodi­ tion-Untersuchungen zur atemregulation m it dem alysis: carbon dioxide flow dependent ventilation. New Engl J mundverschlussdruck. Atemwege-Lungenkrankh, 1985, 11, Med, 1981, 305, 72-75. 336-337. 23. Patterson RW, Nissenson AR, Miller J, Smith RT, Narinss 3. Jordan C.- Assessment of the effects of drugs on respiration. RG, Sullivan SF. - and pulmonary gas exchange Ilr J Anaesth, 1982, 54, 763-782. during hemodialysis. J Appl Physiol: Respirat Environ Exer­ 4. Loeschcke HH. - Weitere untersuchungen uber die almung cise Physiol, 1981, 50, 259-264. in monatlichen zyklus dcr (rau. Pjluegers Arch, 1950, 252, 24. Plotkovski LM, Mannhart 8, Elfassi R, Peslin R, Sadoul 301-311. P. - Role of the mechanical impairment on the ventilatory

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