Download 11. Control of breathing

Contours of Breathing - Control of Breathing
11.1 Control of breathing
Widdicombe JG, Sterling GM. Arch Intern Med 1970l; 126: 311.
Widdicombe JG. Reflex control of breathing, in “Respiratory Physiology” (Widdicombe JG, editor). Butterworths, London, 1974.
Breathing is an autonomous physiological process of which one is not consciously aware.
The movements of breathing are, however, perceptible and can be influenced voluntarily.
Rhythmic impulses from the respiratory centre in the brain descend to various parts of
the respiratory apparatus: the extra-pulmonary and intra-pulmonary airways, the respiratory muscles, the pulmonary vasculature and peripheral chemoreceptors, and to the
cell metabolism. The medullary respiratory centre is itself under the control of impulses
from various parts of the organism:
External (non-respiratory) impulses descending from the associated with movements of
the voluntary muscles (see 11.2 and 11.9).
- Mechanosensors in the lungs, airways and thoracic wall regulate ventilation (mechanical and dynamic aspects of breathing movements; external respiration). These
include stretch sensors, irritant sensors and J-sensors (11.6).
- Chemosensors in the arteries (peripheral chemosensors; 11.5) and the brainstem
(central chemosensors: 11.4) affect the adjustment of ventilation (external respiration) to the needs of the internal environment (“ventilatory drive”) internal respiration (11.10).
- Proprioceptive sensors in the respiratory muscles control contraction at the spinal
level (11.9).
In addition, local mechanisms regulating the passage of the airways (see 11.7 and 11.8)
and the ventilation/perfusion ratio play their part. In widely divergent circumstances,
breathing is highly adapted to the needs of the body (see 1.1 and 1.3).
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J Med 1977; 297: 92-138-194.
Berkenbosch A, Van Dissel J, Olievier CN, de Goede J, Heeringa J. Respir Physiol 1979; 37: 381.
Cunningham DJC, Lloyd BB (editors). The regulation of human respiration. Blackwell, Oxford,
1963.
Derenne JPH, Macklem PT, Roussos CH. Am Rev Resp Dis 1978; 118: 373, 581.
Gold WM. Am Rev Resp Dis 1977; 115: 127.
Grodins FS, Yamashiro SM. Respiratory function of the lung, and its control. Macmillan; New
York, 1978.
Kalia M (organizer). Symposium on central neural mechanism of respiration. Federation Proc
1977; 36: 2365-2432.
Leusen I. Physiol Rev 1972; 52: 1.
Loeschcke HH (editor), Acid-base homeostasis of the brain extracellular fluid and the respiratory
control system. Georg Thieme, Stuttgart, 1976.
Lourenço RV (editor). Chest 1970; 70 (suppl.): 109.
Mitchell RA, Berger AJ. Am Rev Resp Dis 1975; 111: 206.
Porter R (editor). Breathing: Hering Breuer Centenary Symposium. Churchill, London, 1970.
Richardson JB. Am Rev Resp Dis 1979; 119: 785.
Saunders KB. Clinical physiology of the lung. Blackwell, Oxford, 1977
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.2 Neural components
The central regulation of breathing comprises three functionally and anatomically separate elements: (1) voluntary regulation of breathing, originating in the cortex; (2) autonomous regulation, situated in the brain-stem, and (3) integration of respiratory activity,
which occurs in the spinal cord.
The “pneumotaxic centre”, located in the rostral part of the pons cerebri (nucleus
para–brachialis), regulates the breathing pattern by changing the moment at which
inspiration is interrupted. The “apneustic centre” is situated in the formatio reticularis in
the pons, close to the medulla oblongata. It receives information from rostrally situated
centres and from those sited lower in the medulla and spinal cord. The moment of interruption of inspiration is determined by the inflation reflex operating through the vagus
nerve.
Failure of this mechanism causes apneusis, e.g. when the vagus nerve is cut or information from the pneumotaxic centre is interrupted. The moment at which inspiration
is interrupted also depends on the arterial oxygen and carbon dioxide tensions and is
under the influence of stimuli from mechanosensors in the upper airways.
The respiratory neurons of the medullary centre are divided into two groups:
- The dorsal respiratory group (DRG) in the nucleus tractus solitarius (NTS) is the
point of entry for the afferent impulses which influence respiration, for example, the
Hering-Breuer reflex and sniffing reflex (Mitchell). The rhythm generator is probably
located in the vicinity of the DRG. Neuronal activity emanating from this group goes
to the ventral respiratory group and the spinal respiratory motor neurons.
- The ventral respiratory group (VRG) of the nucleus ambiguus (NA) contains motor
neurones of the cranial nerves which govern the accessory breathing muscles. In the
rostral part of the nucleus retro-ambigualis (NRA) these are inspiratory neurons,
with expiratory neurones in the caudal part. The VRG thus contains the motor neurons which govern stimulation, via the spinal cord, of the intercostal and abdominal
respiratory muscles. The VRG neurones are excited by the DRG neurons. The VRG is
situated near the ventro-lateral surface where chemosensitivity is located (Mitchell).
In the spinal cord, the fibres involved in voluntary regulation of breathing are located in
the tractus corticospinalis. Rhythmic impulses from the respiratory neurons in the NRA
follow the antero-lateral paths to the intercostal and abdominal respiratory motor neurones in the thoracic and lumbar regions of the spinal cord. The autonomous non-rhythmic pathways pass on impulses related to the coughing and swallowing reflexes. These
neural activities occur at points separate from the dorsal and ventral respiratory groups.
The paths along which cough stimuli descend are separate from those which innervate
the diaphragm. Hiccoughing is characterized by the simultaneous inhibition of the
expiratory muscles and activation of the inspiratory and laryngeal muscles (Newsom
Davis), resulting in a powerful inspiratory movement against a closed glottis. The central
mechanism of the hiccup is independent of the rhythmic respiratory system.
Central neural activity is integrated in the spinal cord to a rhythmically changing,
spinal activity: during expiration, the inspiratory intercostal neurones are inhibited and
vice versa during inspiration. This alternating active inhibition serves to suppress the proprioceptive reflex stimulus (afferents from muscle spindles) (see 11.9) of antagonist motor neurones when
the agonistic muscle contracts. This intercostal inhibition is thus not the effect of a spinal reflex, as
with other muscle systems; the intercostal system lacks reciprocal inhibition through Iα afferents
(see 11.9).
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J
Med 1977; 297: 92.
Karla M. Fed Proceed 1977; 36: 2405.
Lumscien TJ. J Physiol (Lond.) 1923; 57: 153.
Mitchell RA, Berger AJ. Amer Rev Resp Dis 1975; 111:
206.
Mitchell RA, Herber DA. Brain Res 1974; 75: 345.
Merrill EG. In: “Essays on the nervous system”, Oxford, Clarendon Press, 1974.
Newsom Davis J, Plum F. Exp Neurol 1972; 34: 78.
Nieuwenhuys R, Voogd J, van Huijzen Chr. The
human central nervous system; Springer Verlag,
Berlin, 1978.
Plum F. In: Breathing: Hering-Breuer “Centenary
Symposium” (Porter R., editor), Churchill, London, 1970.
Richter DW, Heyde F, Gabriel M. J Neurophysiol
1975; 38: 1162.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.3 Respiratory rhythm generator
Various hypotheses exist re the mechanism of the respiratory rhythm generator in the
brain, most of them based on special neural networks. In the bi-stable oscillator model, it
is presumed that discharges of impulses develop alternately in groups of inspiratory and
expiratory neurones, grouped in auto-exciting chains and mutually inhibiting each other
(Robson, 1957). The model of inhibitory phasing explains the respiratory rhythm by mutual inhibition of discharging neurones, linked by inhibiting inter-neurons. Interaction
causes the network to discharge synchronously (Mitchell). Von Euler and Trippenbach
(1976) and Feldman and Cohen (1976) have developed a functional model in which the
respiratory rhythm is explained on the basis of inhibition and stimulation of two different neuronal activities; this model is expounded in more detail here.
According to von Euler and Trippenbach, the nucleus tractus solitarius (NTS) contains A-neurones which generate a central inspiratory activity (saw-tooth generator), the
rate of generation of which is strongly influenced by the central and peripheral chemoceptors (chemical drive: CO2, O2, H+) (ventilatory drive). The central inspiratory activity
(CIA) descends in the spinal cord from the A-neurons to the respiratory muscles. This
CIA, together with afferent impulses in the vagus nerve from the pulmonary stretch sensors (breathing pattern), facilitates B-neurons, which are also situated in the NTS. The
combination of the central inspiratory activity and the peripheral vagus activity activates
C-neurones. The latter are “switch-off ” neurons which have an inhibiting effect on the
A-neurones and thereby stop inspiration. The breathing pattern is thus determined by
the central inspiratory activity and the peripheral afferent activity in the vagus nerve. The
location of the C-neurones is still unknown. It is, however, established that neurones in
the nucleus parabrachialis medialis (“pneumotaxic centre”, see 11.2) reduce the threshold value of the C-neurones and thus help to inhibit inspiration. To sum up: inspiration
ends when centrally generated inspiratory activity, combined with afferent activity from
pulmonary stretch sensors, reaches a threshold value. Once stopped, inspiration remains
inhibited throughout the following expiration, duration of expiration being strongly
influenced by various reflexes. The pneumotaxic centre reduces the threshold value of
the switch-off mechanism but does not form part of the oscillating network.
Mitchel RA. Herber DA. Brain Res 1974; 75: 345.
Mitchell RA, Berger AJ. Am Rev Respir Dis 1975; 111: 206.
Merill EG. In: “Essays on the nervous system”. Clarendon Press, Oxford, 1974
Robson JG. In: “Modern Trends in Anaesthesia” (Evans F. T., Gray T. C., editors). Butterworths, London, 1967
Sears TA. Federation Proc 1977; 36: 2412.
Trippenbach T, Milic-Emili J. Federation Proc 1977; 36: 2395.
Woldring S, Dirken MNJ. J Neurophysiol 1951; 14: 227.
References
Bertrand F, Hugelin A. J Neurophysiol 1971; 34: 189.
Cohen MI, Feldman JL. Federation Proc 1977; 36: 2367.
Cohen MI. J Physiol (Lond.) 1971; 217: 133.
Cohen MI. Physiol Reviews 1979; 59: 1105.
Dirken MNJ, Woldring S. J Neurophysiol 1951; 14: 211.
Euler C von, Trippenbach T. Acta Physiol Scand 1976; 97: 175.
Euler C von. Federation Proc 1977; 36: 2375.
Feldman JL, Cohen MI, Wolotsky P. In: „Respiratory centres and afferent systems“ (Duran B.,
editor); Amiens France; Colloque INSERM, pag. 95, 1976
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.4 Central chemosensors
The central chemosensors are undoubtedly the most significant factor in carbon dioxide
transport, but have not yet been histologically identified; their localization is based on
functional measurements (Leusen, Mitchell, Loeschcke, Pappenheimer). Three zones
beneath the ventro-lateral surface of the medulla oblongata have been distinguished: M:
rostral area, S: intermediate area, and L: caudal area.
The rostral and caudal areas are chemosensitive, while the intermediate zone is
probably a junction through which information is sent from chemoreceptors to the more
deeply situated respiratory centres. The central chemosensors react to the hydrogen
ion concentration (cH+) in the extracellular fluid. Stimulation of neurones under the
influence of the cH+ is probably based on facilitation and/or prolongation of cholinergic
transmission (Fukuda and Loeschcke). In contrast to the peripheral ones, the reaction
of the central chemosensors to step-wise changes in Pa,CO2 is relatively slow (minutes),
owing to their site. The gas tensions, blood pH and cerebral blood flow are important for
the external environment of the central chemosensors. Any increase in the Pa,CO2 and/
or reduction in Pa,O2 causes an increase in cerebral perfusion thus in CO2 removal. This
regulating mechanism influences gas exchange in the brain tissue.
Substances important to central chemosensitivity are transported from the blood via
the cerebral extracellular fluid to the cerebrospinal fluid (CSF). If the CSF bicarbonate
concentration is artificially changed (e.g. by artificial perfusion of the ventricles), and
HCO3- gradient arises in the ECF compartment, the depth to the surface of the chemo–
sensors can be calculated by means of the cH+ (pH) gradient thus brought about in the
ECF compartment. The central chemosensors are probably separated by some 100-400
microns from the CSF (Berkenbosch, Berndt).
The permeability of the blood-brain barrier is still the subject of research. It is known
that this barrier is readily permeable to CO2, and it is currently assumed that its permeability to HCO3- ions is much less. For bicarbonate there is a considerable gradient
between blood and ECF, but not between ECF and CSF. Carbon dioxide and bicarbonate
ions easily exchange between extracellular brain fluid and cerebrospinal fluid. However,
changes in CSF bicarbonate may lag a little behind those in the ECF. In the event of
sudden changes in Pa,CO2 (respiratory disturbance), changes in PCO2 and PCO2,CSF occur
rapidly, accompanied by changes in pH. In cases of rapid change in HCO3- in the blood
(non-respiratory disturbance) there are no equally rapid changes in CSF bicarbonate (see
11.17).
The ECF cH+ depends on many factors: arterial and venous blood gas values, intracellular buffering of H+, selective transport through the blood-brain barrier, potential
difference between blood and CSF and changes in cellular (H+) resulting from cellular
metabolism (e.g. formation of lactate in hypoxia). A change of 0.01 of pH unit at the
central chemosensors causes a change in ventilation of about 3 L/min and is equivalent
to a change in PCO2 of 1 mmHg (0.133 kPa).
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J Med 1977; 297: 92.
Berkenbosch A, de Goede J, Olievier CN, Quanjer PhH. Respir Physiol 1972; 35: 215.
Cameron IR. The central chemical regulation of breathing. In: “Modern Trends in Physiology 1972; 1: 268.
Dermietzel R. In: “Acid-base homeostasis of the brain extra-cellular fluid and the respiratory control system,
1976.
Fukuda Y, Loeschcke HH. Pflügers Arch 1979; 379: 125.
Heeringa J..; Peripheral chemoreceptors and the ventilatory response to CO2 during hyperoxia. Thesis, Leiden,
1979.
Leusen I. Am J Physiol 1954; 176: 39.
Loeschcke HH. Acid-Base homeostasis of the brain extracellular fluid and the respiratory control system. Symposium Bochum 1975. Georg Thieme, Stuttgart, 1976.
Mitchell RA, et al. J Appl Physiol 1963; 18: 523.
Pappenheimer JR, et al. Am J Physiol 1965; 208: 436.
Saunders KB. Clinical Physiology of the Lung. Blackwell, Oxford, 1977,
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.5 Peripheral chemosensors
The peripheral chemosensors are situated in the carotid body at the bifurcation of the
common carotid artery. The sensors in the aortic body are probably not significant; at the
most there is slight sensitivity to varying CO2 tensions (Hanson). The chemosensors of
the carotid body are highly sensitive to the oxygen tension in arterial blood, and less so,
to the carbon dioxide tension. The chemosensors are also sensitive to the blood pressure
and to rate of blood flow through the carotid body. The chemical stimuli are converted to
electrical impulses which then ascend along the afferent fibres (myelinated and non-myelinated) of the carotid sinus nerve and the glossopharyngeal nerve to the medullary
regulatory centre. The contribution of the peripheral chemosensors to the regulation of
breathing is some 20-50% of the total.
The mechanism of oxygen sensitivity is still obscure. It is unlikely to be triggered by
a deficit of oxygen in the tissue of the sensor: the considerable blood flow (2 L per 100 g
of tissue a minute) results in a very small a-v difference, despite the metabolism at that
point being the highest in the body. The nerve fibres in the carotid body form reciprocal
synapses with the carotid body cells; i.e. these cells are both pre- and post-synaptic with
respect to the afferent nerves. According to McDonald and Mitchell the carotid body cell
is a dopaminergic inhibitory interneuron which modulates the generation of impulses
in the afferent nerve endings. The chemosensor is thus not the carotid body cell but the
nerve ending: impulses reaching the nerve endings release a transmitter which stimulates the carotid body cell to release dopamine, a substance which again inhibits the
nerve ending. The efferent nerve fibres have an inhibiting effect on chemosensor impulse
frequency in the afferent fibres, this inhibiting effect increasing with efferent impulse
frequency (negative feedback).
Under steady-state conditions, the relationship between chemosensor discharge
(impulse frequency) and chemostimulation through the blood is as follows: The impulse frequency rises hyperbolically as the Pa,O2 falls. The effects of changes in Pa,O2 are
strongest in the range from 13 to 4 kPa (100-30 mmHg). The impulse frequency rises
linearly with the Pa,CO2 and [H+]. These stimuli are probably independent, but potentate
each other. The carbon dioxide sensitivity is probably also based on detection of change
in H+ concentration: pH changes of 7.45 to 7.25 at the peripheral chemosensors bring
about an approximate doubling of ventilation. Sensitivity to CO2 is of particular importance at low oxygen tensions, when the PCO2 and PO2 effects reinforce each other. The
cumulative effects of changes in Pa,CO2 and Pa,O2 result in a curvilinear relationship
between impulse frequency and Pa,CO2.
n normal circumstances, alveolar gas tensions oscillate by about 0.3 to 0.4 kPa (2-3
mmHg) (Yokota and Kreuzer). These oscillations are reflected in the impulse frequency
in nerve fibres coming from the chemosensors. According to some authors (Biscoe and
Purves), fluctuations in the blood gas tensions strengthen the chemosensor discharge
and thus contribute to the regulation of breathing; this point is, however, still controver-
sial. The reaction to oscillations in oxygen is much slower than to those in carbon dioxide. The time
relationship between oscillation and breathing phase (inspiration-expiration) determines the effect
(Ward). It is not yet known in how far synchronisation between peripheral and central chemosensors plays a part in the regulation of breathing; blood circulation-time is also involved. Indeed,
synchronisation of chemosensors is a very complicated matter (Cunningham).
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl
J Med 1977; 297: 92.
Biscoe T. J., Purves MJ. J Physiol 1965; 190: 389.
Black AMS, Torrance RW. Respir Physiol 1971; 13:
221.
Cunningham DJC. Nature 1975; 253: 440.
Hanson MA, Rao PS, Torrance RW. Respir Physiol
1979; 36: 301.
McDonald DM, Mitchell RA. J Neurocytol 1975; 4:
177.
Murray JF; The normal lung. W. B. Saunders, Philadelphia, 1976
Saunders KB. Clinical physiology of the lung. Blackwell, Oxford, 1977
Ward SA, Drysdale DB, Cunningham DJC, Petersen
ES. Respir Physiol 1979; 36: 311.
Yokota H, Kreuzer F. Pflügers Arch 1973; 340: 291.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.6 Sensors in lungs and airways
The extrathoracic airways contain chemosensors and mechanosensors, the afferent
nerve fibres of which run through the trigeminal and olfactory nerves and (from the
larynx and pharynx) the glossopharyngeal and superior laryngeal nerves. Stimulation
of sensors in the nose causes inhibition of breathing (expiratory apnoea), bradycardia
and bronchoconstriction. The sneezing reflex is possibly caused by stimulation of these
sensors; sneezing is the result of a powerful reflex activity of the medullary expiratory
neurons after previous deep inspiration. Stimulation of sensors in the pharynx produces
reflex stimulation of the inspiratory medullary neurons (aspiration reflex). The cough reflex is caused by stimulation of rapidly-adapting mechanosensors in the larynx, trachea
and major intrapulmonary airways. In coughing, a strong inspiration is followed by a
strong expiration, initially against a closed glottis, which then suddenly opens, resulting
in an explosive expiration.
Bronchial irritant sensors are rapidly-adapting and can be observed in the tracheal
epithelium as far down as the bronchioles (Widdicombe). The myelinated afferent fibres
run in the vagus nerve. The nerve endings are just under the ciliary surface and are affected by (1) chemical, pharmacological and mechanical stimuli; (2) rapid changes in the
bronchial dimensions: deflation, inflation, coughing, and (3) mechanical deformation
of the lungs and airways: pneumothorax, atelectasis, embolism. The effects of stimulation are: hyperpnoea, bronchoconstriction, coughing and laryngoconstriction (see also
11.23). Irritant sensors play an important part in the mechanism of the Hering-Breuer
deflation reflex. The irritant sensor reflex has two positive feed-back mechanisms: (1)
sensor stimulation causes hyperventilation, which itself further stimulates the sensors,
and (2) stimulation causes bronchoconstriction, which further stimulates the sensors.
The pulmonary stretch sensors are probably located in the smooth musculature of the
trachea and downwards into the bronchioles. They are stimulated by inflation of the lung
and are slow to adapt. The large myelinated afferent fibres are situated in the vagus nerve.
Stimulation of the pulmonary stretch sensors causes the Hering-Breuer inflation reflex:
inhibition of central inspiratory activity and an increase in expiration time, with bronchodilation, tachycardia, vasoconstriction and dilatation of the larynx. This reflex regulates
the breathing pattern. In man the Hering-Breuer reflex has a high activation threshold:
it comes into play only with increased ventilation (physical exertion) and in pathological conditions (see 11.12). There are indications that when the Pa,CO2 rises, the stretch
sensors become less sensitive. These sensors also play a part in the broncho-muscular
control of the patency of the airways: hyperinflation causes not only mechanical but also
reflex dilatation of the airways.
The alveolar juxta-capillary sensors (J-sensors) are situated in the walls of the alveolar
capillaries (Paintal). The axons are in close relationship with the capillary endothelial
cells. The afferent, slowly-conducting, non-myelinised fibres are situated in the vagus
nerve. J-sensors are stimulated when the quantity of interstitial fluid in the lung increas-
es, e.g. during exercise, pulmonary oedema, pulmonary obstruction or embolism. J-sensors are also
stimulated by the injection of histamine and lobeline into the pulmonary circulation. Stimulation
results in tachypnoea, bronchoconstriction and bradycardia and, in man, probably coughing as
well. J-sensors can be regarded as belonging to the nociceptive system of the lungs and airways and,
due to their position, respond exclusively in pathological conditions in the alveoli. For this reason,
a better name would be alveolar nociceptive sensors (Widdicombe). The “J reflex” comprises the
reduction of the contraction power of the skeletal muscles by reflex inhibition of the spinal mono–
synaptic reflex; i.e. physical work is limited (Deshpande). Deflation of the lung causes superficial
breathing, bradycardia and hypotension. The deflation reflex occurs especially in patients with
reduced lung volume, and is probably caused by stimulation of the alveolar nociceptive sensors.
References on next age
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J Med 1977; 297: 92.
Clark FJ, von Euler C. J Physiol (London) 1972; 222: 267.
Derenne JPh, Macklem PT, Roussos CH. Am Rev Resp Dis 1978; 118: 373.
Desphande SS, Devanandan MS. J Physiol (London) 1970; 206: 345.
Euler von C, Herrero F, Wexler I. Respir Physiol 1970; 10: 93.
Fillenz M, Widdicombe JG. Enteroreceptors. In: Handbook of Sensory Physiology vol. III/1, (Neill
E, editor); Springer Verlag, Berlin, 1972.
Gold WM. Am Rev Resp Dis 1977; 115: 127.
Karczewski W, Widdicombe JG. J Physiol (London) 1969; 201: 293.
Knowlton GC, Larrabee MG. Am J Physiol 1946; 147: 100.
Paintal AS. Physiol Rev 1973; 53: 159.
Paintal AS. In: Breathing. Ciba Foundation Hering-Breuer Centenary Symposium (Porter R, editor). Churchill, London, 1970.
Richardson JB. Am Rev Resp Dis 1979; 119: 785.
Richardson JB, Ferguson CC. Federation Proc 1979; 38: 202.
Sant’Ambrosio F, Sant’Ambrosio G, Mortola JP. Respir Physiol 1979; 36: 327.
Sellick H, Widdicombe JG. J Appl Physiol 1972; 31: 15.
Stransky A, Szereda-Przestaszewska M, Widdicombe JG. J Physiol (London) 1973; 231: 417.
Widdicombe JG. Reflex control of breathing. In: “Respiratory Physiology” M. T. P. International
Review of Science: Ser. 1, vol. 2, Butterworth, London, 1974.
Widdicombe JG. Physiol Rev 1963; 43: 1.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.7 Control of airway patency
The tone of the bronchial muscles is largely determined by the action of the autonomic
nervous system. The efferent parasympathetic fibres from the dorsal motor nucleus of
the vagus nerve descend straight to the airways as pre-ganglionic fibres, or to the para–
sympathetic plexus in the hilus, whence post-ganglionic fibres go to the bronchi and
blood-vessels. The sympathetic fibres at the level of T1 - T4 go to the stellate ganglion
or the middle cervical ganglion, whence post-ganglionic fibres descend to the airways
and blood vessels. The parasympathetic cholinergic fibres run mainly in the walls of
the bronchi, and the sympathetic fibres mainly in the accompanying blood vessels.
Sympathetic and parasympathetic fibres are connected to each other both centrally
and peripherally. In man, no adrenergic fibres have yet been found in the trachea and
large airways. The bronchial muscles in man show many links between the muscle cells.
These are important for the transmission of electrical signals: the bronchial muscles
have an intrinsic activity which is influenced by extrinsic innervation (sympathetic and
parasympathetic).
In the control of bronchial tone, the bronchoconstricting effect of the cholinergic
fibres of the parasympathic innervation is predominant. The stretch sensors, J-sensors
and irritant sensors form part of the parasympathetic system. The following bronchoconstricting transmitters are of significance here: acetylcholine (ACh), methacholine,
histamine and prostaglandins (see 11.8). Bronchoconstriction is prevented by the
administration of atropine. Stimulation of the sympathetic system (e.g. the stellate ganglion) causes bronchodilation. The stimulus acts directly on the β-adrenergic receptors
of the smooth muscles or indirectly on the α-receptors of the cervical ganglia. The effect
on the β-receptors can be blocked with propranolol. In normal persons both atropine
and the sympatheticomimetics which do not act on secretion (adrenaline, noradrenaline, isoprenaline) cause bronchodilation, demonstrating that bronchial tone exists even
during normal quiet breathing. According to Szentivanyi, bronchial hyperreactivity is
the result of a partial blockade of β-receptors.
The functional consequences of an alteration in bronchial tone depend on the site
at which change takes place. Bronchoconstriction of the large airways is usually the
result of neural stimulation and mainly causes changes in flow resistance in the airways.
Bronchoconstriction of the small airways, down to alveolar level, is due to humoral factors (e.g. histamine, prostaglandins, oxygen, carbon dioxide); the predominant changes
here are in lung volume, compliance and the frequency-dependence of the compliance.
A high carbon dioxide content in the respiratory gas has no perceptible effect on
flow resistance in the airways of healthy persons, but in asthmatic subjects it is associated with a slight increase in the patency of the airways. In healthy persons, hypocapnia leads to narrowing of the airways. This effect can be reversed by atropine, which
indicates that bronchoconstriction is caused by neural and humoral mechanisms. A
low oxygen content in the breathing gas acts directly on the bronchial muscles and in
normal persons causes very slight constriction of the bronchi. Local regulation of the ventilation/
perfusion ratio is linked with this effect of the respiratory gases on flow resistance in the airways.
The pulmonary circulation is under the influence of the autonomic nervous system: in normal
circumstances there is a slight vascular tone which is reduced by the administration of acetylcholine. In addition, oxygen has a direct effect on the pulmonary circulation; the effect of CO2 is not
certain. The pulmonary haemodynamics may well influence breathing through reflexes from the
sensors in the lung parenchyma.
References:
Cunningham DJC, Lloyd BB. The regulation of human respiration. Blackwell, Oxford, 1963.
Guz A, Noble MIM, Trenchard D, Mushin WW, Makey AR. Clin Sci 1966; 30: 161.
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G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
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G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.8 Bronchial regulation
Regulation of the bronchi at cellular level is influenced by airborne, neural and humoral (metabolic) factors. The mast cells, as primary effector cells, occupy a central place.
Mast cells develop from primitive mesenchymal cells which differentiate under neural
ectoderm influence. Mast cells are situated in the bronchial mucosa, but they also occur
in the bronchial lumen. In normal circumstances, this cell, as a secretory element, plays
an important part in local immunity. In addition, the mast cell is regarded as the local
regulator of bronchial homoeostasis. Under the influence of sympathetic and parasympathetic drugs, allergens and metabolic substances, the mast cell produces various
primary mediators and acts as a “chemical amplifier”. The primary mediators stimulate
the irritant sensors and increase bronchial permeability by their effects on the “tight
junctions”. In this way, an antigen can penetrate deeper into the body. Because of the
increased permeability, an abnormally large amount of histamine reaches the bronchial
muscles. These mechanisms play a part in hyperreactivity.
- Histamine acts directly on the smooth bronchial muscles (contraction), stimulates
the irritant sensors (vagus nerve) and causes an increase in permeability of the small
blood vessels (veins and capillaries). The effect of histamine on the bronchial muscles
is twofold: stimulation of H1 receptors, causing contraction, and stimulation of H2
receptors, causing relaxation.
- The slow reacting substance of anaphylaxis (SRS-A) acts directly on the smooth
bronchial muscles and causes bronchoconstriction. It also increases the permeability
of small blood vessels (veins and capillaries).
- Prostaglandins are formed in the bronchi as a result of antigen-antibody reactions.
PGF2 probably acts directly on the bronchial muscles and causes constriction of the
bronchi; PGE causes dilatation of the bronchi. Prostaglandins regulate the tone of the
bronchial muscles and probably also the pulmonary vascular resistance. It is possible
that both substances control the release of primary mediators (Mathe).
Bradykinin stimulates the irritant sensors, causing a bronchoconstriction reflex. Bradykinin increases the permeability of the venous blood vessels. Cyclic AMP and cyclic
GMP are secondary mediators: cAMP probably has a relaxing effect by influencing intracellular Ca2+ distribution. cGMP possibly inhibits the muscle contraction which occurs
under the influence of humoral stimuli (Schultz). Sodium cromoglycate stabilises the
mast cells and thus inhibits the release of mediators (Orr). It may be that this substance
also reduces the activity of the irritant sensors.
References
Austen KF, Orange RP. Am Rev Resp Dis 1975; 112: 423.
Daems WTh, Quanjer PhH, Reerink-Brongers EE (editors). The mast cell in relation to allergic
mechanisms. Netherlands Asthma Foundation, Leusden, 1977.
Gold WM. Am Rev Resp Dis 1977; 115: 127.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.9 Regulation of respiratory muscles
Respiratory muscles are striated and have two types of proprioceptive sensors: muscle spindles and tendon sensors. Both play a part in regulating muscular tone through
coordinating centres in the spinal cord. The afferent nerve fibres enter the spinal cord
dorsally and form part of a neural network which receives impulses from higher and
lower levels. These neural interactions determine the efferent motor activity out to the
various respiratory muscles.
The muscles of respiration contain extrafusal fibres for muscle contraction and
intrafusal fibres which, together with the endplates (muscle spindles), regulate the
contracting power of the respiratory muscles to the required breathing movement of
the thorax. The extrafusal fibres are innervated by myelinated α-motor neurons and the
intrafusal fibres by non-myelinated γ-motor neurons. The sensors in the muscle spindles
are linked by the Iα afferent neurons with the α-motor neurons (A). The mechanism of
action is as follows. The ventilation impulse from the formatio reticularis activates both
α and γ-motor neurons. The activity in the γ-motor neurons causes contraction of the
intrafusal fibres, with the result that the end plates of the muscle spindles are stimulated
(B). The activity in the α-motor neurones causes shortening of the extrafusal fibres, reducing tension in the muscle spindles and diminishing stimulation of the end plate (C).
The discharge of these sensors is proportionate to the difference in shortening between
the extrafusal and intrafusal fibres. Muscle spindles not only affect the (voluntary) fine
control of the respiratory muscles, they are also important in the perception of breathing.
Tendon sensors (Golgi receptors) keep the respiratory muscles at constant tension,
adapted to circumstances. Muscle spindles and tendon sensors influence muscle contraction in opposite ways: muscle spindles cause the muscle power to increase on stretching
(facilitation), while tendon sensors inhibit muscle contraction. The respiratory muscles
are involved in control of breathing in various ways connected with differences in the
numbers of muscle and tendon sensors. The diaphragm contains a limited number of
muscle spindles and many tendon sensors, indicating that this muscle is responsible for
autonomous “overall” breathing, without fine regulation. The intercostal muscles, however, have many muscle spindles and relatively few tendon sensors, and contribute to the
(voluntary) adaptation of breathing to the body condition.
According to Campbell and Howell, breathing is consciously perceived when a lack of
proportion occurs between the breathing volume (breathing flow) and muscle tension.
Muscle spindles play an important part in this respect. The significance of rapid adaption
through proprioceptive sensors in the relatively slow breathing movements is not yet
known.
References
Derenne JPh, Macklem PT, Roussos CH. Am Rev Resp Dis 1978; 118; 373.
Derenne JPh, Macklem PT, Roussos CH. Am Rev Resp Dis 1978; 118: 581.
Howell JBL, Campbell EJM (editors). Breathlessness. Blackwell, Oxford, 1966.
Jung-Caillol MC, Duron B. In: “Respiratory centers and afferent systems (Duron B, editor); Inserm, Paris,
1976.
Newsom Davis J. Control of the muscles of breathing. In: Respiration Physiology (Widdicombe JG, editor).
Butterworths, London, 1974.
Nunn JF. Applied respiratory physiology. Butterworths, London, 1969.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.10 Central inspiratory activity
The level of central respiratory activity can be deduced from measurements at various
levels of the breathing process.
- The electrical activity in the phrenic nerve directly reflects the central neural breathing activity (ENG: electroneurogram). Indices of this activity comprise the number of
impulses per breath, the impulse frequency during the inspiratory peak flow, or the
average activity per 0.1 second. This method has not yet reached the stage of clinical
application.
- The electromyogram (EMG) is a measure of the muscular activity (muscle metabolism). The relationship between muscle metabolism and contraction power (mechanical activity) is related to power-length and power-velocity ratios. The relationship
between the EMG and the mechanical effect thus depends on factors such as volume
and shape of thorax. In mechanically normal breathing there is no need to replace the
ventilatory output by using the EMG.
In mechanical impairment, however, the EMG can provide useful information, especially about the occurrence of respiratory insufficiency due to muscular exhaustion
(Lindström). The EMG at the diaphragm, measured with an esophageal electrode, is
a reasonably good indicator of central respiratory activity. The current peak-average
and current time-average are useful for estimating the electrical activity of the diaphragm and thus, indirectly, of the central respiratory activity. The absolute value of
the above indices is difficult to interpret, but in man they can be used to demonstrate
changes in the activity of the diaphragm, e.g. resulting from chemical or mechanical
stimulation of breathing. The diaphragm EMG is a good estimate of central neural
activity in the determination of hypoxic and hypercapnic chemosensitivity in man
(Lopata).
- The intrathoracic pressure measured during inspiration is indirect estimate of central
respiratory activity. However the transformation of neural activity into muscle activity, and further of muscle tension into thoracic pressure, depends on many factors
such as muscle length, rate and extent of muscle contraction, and impedance of the
respiratory system. Thus the intrathoracic inspiratory pressure provides only indirect
information on central inspiratory activity.
- The inspiratory closing pressure at the mouth is a good estimate of central inspiratory
activity, because the lung volume remains constant during measurement, the muscle
length does not alter, viscous and elastic resistance is not involved, and there is no
inflation reflex (see 11.20).
.
- The mean inspiratory flow is a measure of central inspiratory activity: VI = VI /tI .
The ventilation is regulated by changes in the central inspiratory activity, and thus
indirectly reflects this neural output (von Euler, Milic-Emili). Instead of ventilation,
work of breathing, measured by the esophageal pressure method or calculated from
oxygen consumption, can be taken as an estimate of the central respiratory output.
References
Derenne J.P, Macklem PT, Roussos CH. Am Rev Resp Dis 1978; 118: 373.
Derenne JP. Bull Europ Physiopathol Resp 1977; 13: 681.
Eldridge FL. Chest 1976; 70 (suppl.), 154, 1976
Lindström L, Kadefors R, Petersen I. J Appl Physiol REEP 1977; 43: 750.
Lopata M, Evanich MJ, Lourenço RV. Chest 1976; 70 (suppl.): 162.
Lopata M, Zubillaga G, Evanich MJ, Lourenço RV. J Lab Clin Med 1978; 91: 698.
Mead J. Chest 1976; 70 (suppl.): 149.
Milic-Emili J, Grunstein MM. Chest 1976; 70 (suppl.): 131.
Sharp JT, Druz W, Danon J, Kim MJ. Chest 1976; 70 (suppl.): 150.
Von Euler C, Herrero F, Wexler I. Respir Physiol 197-; 10: 93.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.11 Ventilation and breathing pattern
Central inspiratory activity (“ventilatory drive”) is regulated to the needs of the body by
means of chemosensors (humoral regulation). Any increase in this activity results in a
more vigorous and rapid inspiration and a rise in inspiratory volume. The latter enhances increased stimulation of stretch sensors and the consequent inflation reflex causes the
central inspiratory activity to be broken off earlier, resulting in an increase in respiratory
frequency. Thus the increase in breathing volume is reinforced by an increase in breathing frequency. The breathing pattern is thus controlled by the mechano-sensor reflexes.
During a breathing cycle, the following mechanisms come successively into play:
Phase-switch expiration-inspiration behaves as an on-off mechanism. The cumulative
neural information regarding lung volume during the previous expiration (mecha–
nosensors) determines the instant of phase-switch.
- The mean inspiratory flow, i.e. the quotient of the inspiratory volume and the inspiration time is a measure of central inspiratory activity (“ventilatory drive”). The
inspiratory activity remains constant during the inspiration (on-off mechanism) and
is determined by the humoral stimulation of breathing (chemosensors).
- The duration of inspiration (tI) depends on the moment at which inspiration is interrupted.
- The threshold value of the interruption of inspiration (inspiration-expiration phaseswitch) is determined by the characteristics of the respiratory rhythm generator. The
relationship between inspiration volume VI and inspiration time tI in animals is a
hyperbolic curve: the longer the tI, the smaller the VI needed to end tI. The curve is
made up of the points where the inflation reflex (vagus reflex) interrupts inspiration.
In slight inspiratory activity, i.e. during slow breathing, inspiration can last so long
that it is switched off by the rhythm generator before it is via the inflation reflex (von
Euler), This also happens when the vagus nerve is cut. In such cases the breathing
frequency is determined only by the periodicity of the respiratory rhythm generator.
- Expiration occurs through the potential energy in the respiratory system at the end
of an inspiration. The expiratory volume flow is mechanically “braked” by the resistance in the airways, especially in the larynx. Inhibition also results from the antagonistic activity of the inspiratory muscles (see 11.9), which show some activity even
during expiration. The expiratory flow is relayed to the respiratory centres through
the vagus nerve. The expiratory flow is also regulated by changes in the patency of the
larynx (cricothyroid muscles). The threshold value of cricothyroid activity is reduced
in hypercapnia and raised in hypocapnia (Horiuchi). The duration of expiration is
also regulated by the motor activity of the diaphragm (inspiratory musculature).
Thus a feed back mechanism continuously keeps expiration at the required value. In
the case of severe mechanical obstruction, motor activity of the expiratory muscles
rises expiratory volume flow above the passive expiratory “collapse flow”.
References
Clark FJ. Von Euler C. J Physiol 1972; 222: 267.
Cotes JE, Johnson GR, Reed JW, et al. Bull Physiopath Resp 1975; 11: 115.
Cunningham DJC, Pearson SM, Gardner WN. Arch Fisiol 1972; 69 (suppl.): 443.
Derenne JPh, Macklem RT, Roussos CH. Am Rev Resp Dis 1978; 118: 373.
Gautier H. J Physiol (Paris) 1969; 61: 31.
Horiuchi M, Sasaki CT. Ann Otol Rhinol Laryngol 1978; 87: 386.
Jammes Y, Auran Y, Gouvernet J, Delpierre S, Grimaud C. Bull Europ Physiopath Resp 1979; 15: 527.
Remmers JE. Chest 1976; 70 (suppl.); 134.
Von Euler C, Herrero F, Wexler I. Resp Physiol 1970; 10: 93.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.12 Ventilation and breathing pattern
The model of the control of breathing is based on animal experiments, but can be used
in clinical studies. In man the inspiratory switch-off time at rest is determined by the
central rhythm generator and not by the vagus reflex. During quiet breathing the switchoff point is under the Vt - t1 hyperbola and the relationship between VI and t1 is linear.
Therefore any increase in breathing volume is accompanied by a reduction in breathing
frequency, as long as the area of the hyperbola (vagus reflex) is not reached. For this
reason, vagus blockade in man, does not influence the pattern of quiet breathing. In the
case of increased ventilation, the point of interruption of inspiration moves along the
line of the hyperbola, and breathing frequency increases with breathing volume, due
to increased stimulation of stretch sensors. This determines the breathing patterns as it
occurs during effort, hypercapnia and hypoxia, i.e. circumstances involving increased inspiratory activity. The above neural model of regulation is the alternative of the mechanical model, in which it is assumed that the breathing pattern is regulated in such a way
that work of breathing is minimal to meet the demands of the body (see 11.24).
During quiet breathing in normal individuals, the central inspiratory activity
(ventilatory drive) is fairly constant, changes in the breathing pattern being the result
of variations in the central inspiratory switch-off time. Besides, the extent of the expiratory inhibition plays a contributing part: (A) shows the situation without expiratory
inhibition; in (B), expiration is regulated to keep the expiratory flow constant. During
sleep (C) the central inspiratory switch-off time is delayed, but the ratio between VI and
t1remains unchanged. Sleep thus causes an increase in VI in proportion to the duration
of the inspiratory phase; the mean inspiratory flow changes little. Jammes and coworkers
showed that in man, VI increases proportionally to body height: VI and fR depend on age
and sex. In young adults, VI reaches a maximum and fR a minimum. The VI/t1 ratio is
not age dependent.
In hypercapnia (D) the tidal volume (VI) increases, with no alteration in tI. Stimulation of the chemosensors results in increased central inspiratory activity with no alteration in inspiration time. In addition, expiratory inhibition is cancelled by suppression of
inspiratory activity during the expiration phase; expiration is even accelerated by central
expiratory activity. Thus the expiration time as well as the breathing frequency remain
unaltered.
Hypoxia (E) has the same effect as hypercapnia on the central inspiratory activity and
expiratory inhibition, but shortens the inspiration time (t1) as well as the expiration time
(tE) resulting in an increase in breathing frequency.
Decima EE, von Euler C. Acta Physiol Scand 1969; 75: 568.
Decima EE, von Euler C. Acta Physiol Scand 1969; 75: 580.
Jammes Y, et al. Bull Europ Physiopath Respir 1979; 15: 527.
Koehler RC, Bishop B. J Appl Physiol REEP 1979; 46: 730.
Remmers JE, Bartlett Jr, D. J Appl Physiol REEP 1977; 42: 80.
Remmers JE. Analysis of ventilatory response. Chest 1976; 70 (suppl.): 134.
Von Euler C, Herrero F, Wexler I. Resp Physiol 1970; 10: 93.
References
Bouhuys A. Breathing. Grune and Stratton, New York, 1974.
Campbell EJM, Agostoni E, Newsom Davis J. The respiratory muscles (2nd edition), W.B. Saunders
Company, Philadelphia, 1970. 1970.
Clark FJ, von Euler C. J Physiol (Lond.) 1972; 222: 267.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.13 Regulation of carbon dioxide transport I
The humoral regulation of respiration is achieved by means of chemosensors. The
peripheral chemosensors are sensitive to oxygen and carbon dioxide; their responses to
changes in blood gas tensions are relatively rapid, the chemosensitive stimuli being transmitted to the medullary rhythm generator by the vagus and glossopharyngeal nerves (see
11.5). The central chemosensors are sensitive to changes in acidity in the extracellular
brain compartment (see 11.4). These changes are linked with the partial pressure of
carbon dioxide in the adjacent compartments containing blood and cerebrospinal fluid.
The central chemosensors only register comparatively slow changes in the acid-base
balance in their environment. This information is passed to the medullary processing
unit (rhythm generator), whose tissues are sensitive to any reduction in oxygen tension.
Impulses from the medullary centre descend to the respiratory muscles, ventilation thus
being adjusted to metabolic requirements. A distinction must be made between the
controlling system (chemosensors and medullary processing unit) and the system which
is controlled (the respiratory muscles, ventilation and gas exchange).
In the controlling system, the blood gas level (PCO2) is the independent
variable
.
(input) and the central respiratory activity, shown as ventilation (V), is the dependent
variable. In the graph, PCO2 is shown on the x axis and on the y axis;
. there is a linear
relationship between them. The slope of the CO2 response curve V/PCO2 line) is an indication of the sensitivity of the controlling .system to CO2.
In the controlled system, ventilation (V) is the independent variable (input) and
carbon dioxide tension the dependent variable (output). The relationship between ven.
tilation,
carbon dioxide tension and CO2 transport can be represented as follows: nCO2
.
= V x PCO2 / PB. When CO2 transport and barometric pressure (PB) are unchanged, the
product is a constant, and the relationship between the two is the so-called metabolic .
hyperbola. A hyperbolic relationship can also be recognized as follows: as ventilation (V)
tends towards infinity, PCO2) is the independent variable (input) and the central respiratory activity, shown as ventil tends towards zero, and if ventilation tends towards zero,
PCO2) is the independent variable (input) and the central respiratory activity, shown
as ventilbecomes infinite. The respiratory regulating system as a whole must fulfill the
functions of both subsystems. If the axes of the metabolic hyperbola (controlled system)
are exchanged, both functions can be shown on one graph. The point of intersection of
carbon dioxide tension and ventilation is the set point for the regulation of breathing.
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J Med 1977; 297: 92.
Eger EI, et al. J Appl Physiol 1968; 24: 607.
Fencl V. Chest 1976; 70 (suppl.): 113.
Kronenberg R, Hamilton FN, Gabel R, et al. Respir Physiol 1972; 16: 109.
Lloyd BB, Jukes MGM, Cunningham DJC. Quart J Exp Physiol 1958; 43: 214.
Saunders KB. Clinical Physiology of the Lung, Blackwell, Oxford, 1977
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.14 Regulation of carbon dioxide transport II
Controlling system: The slope of the CO2 response curve is a measure of the sensitivity to
CO2 of the controlling system (see 11.13). The steeper the curve, the greater the sensiti–
vity to CO2; any change in CO2 transport being accompanied by a smaller change in the
PCO2. The following factors are involved:
- Oxygenation of the blood at the site of the chemosensors and respiratory centres
(A). In hyperoxia, oxygen stimulation from the peripheral chemosensors is nil, and
the sensitivity to CO2 is less than in normoxia. In hypoxia, oxygen stimulation plays
a contributory part and the sensitivity to CO2 is above normal (Lloyd). The normal
.
ventilatory sponse to CO2 (V) in young adults is 26 L/min per kPa of carbon dioxide
pressure difference (3.5 L/min per mmHg) (Berger), but the range is wide.
- The acid-base balance of the organism (B), in metabolic acidosis the CO2 response
line shifts to the left and the carbon dioxide pressure decreases. The new set-point of
breathing is found along the shifted CO2 response line.
- Age (C): sensitivity to CO2 decreases with age; at 70, it is 14 L/min per kPa (1.9 L/
min per mmHg) (Kronenberg).
are “loaded”. Ventilation reacts more slowly to a step-wise rise in CO2 tension in the inspired gas
than to equivalent sudden fall. This difference in response can be explained as follows. When the
PI,CO2 rises suddenly, ventilation is stimulated via the peripheral and central chemosensors; CO2
retention is counteracted by the increased breathing; in consequence equilibrium is attained rather
slowly. On the other hand, if the PI,CO2 falls, a high initial level of ventilation is present, so that net
excretion of CO2 is very large; balance can thus be reached very quickly.
References: See 11.13
.
Controlled system. The position of the metabolic hyperbola in the V-PCO2 diagram
(see 11.13) is determined by the CO2 content of the inspired gas, the volume of the dead
space, and the extent of CO2 transport:
.
- A rise in the CO2 pressure in the inspired gas (D) shifts the vertical asymptote (V =
∞) towards the carbon dioxide tension in the inspired gas: the hyperbola is. shifted
parallel to the PCO2 axis, the CO2 tension of the blood increases, and the V-PCO2
point no longer falls on the normal CO2 response line. This is corrected by the
controlling system, so that the intercept of the CO2 response line with the displaced
metabolic hyperbola is again achieved. This is the new set point of breathing, with
.
increases in both PCO2 and V.
- Any increase in the dead space (E) will shift the horizontal asymptote towards the
value
. of the dead space ventilation. The metabolic hyperbola moves parallel to the
V-axis, the direct result being an increase in PCO2. The set point of breathing thus
moves away from the CO2 response line. The controlling system shifts the set point
along the displaced metabolic hyperbola
. until intersection with the CO2 response
line is again achieved: both PCO2 and V are increased.
- Increase of the carbon dioxide transport (F), occurring during physical exertion and
hyperthermia, affects the curvature of the metabolic hyperbola and moves it away
from both asymptotes. The set point of breathing shifts along the CO2 response curve
until the intersection with the displaced hyperbola is reached again.
If the arterial CO2 tension is suddenly raised and maintained at that level, e.g. by inhalation of CO2, there is a full response of the peripheral chemosensor within a few seconds.
The central chemosensor response takes several minutes to develop to its full extent,
because the PCO2 in the interstitial fluid reaches its final value when these compartments
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.15 Measurement of carbon dioxide sensitivity
The sensitivity of the respiratory system to carbon dioxide is estimated from the effect
of a carbon dioxide stimulus on the ventilation. This method is one of the few available for use in routine clinical examinations. Measurement is usually carried out during
hyperoxia in order to eliminate the oxygen stimulus. This has the disadvantage that the
results are not the same as those obtained during normoxia. In cats, about a third of the
sensitivity to CO2 is dependent on the peripheral chemosensors and two-thirds on the
central chemosensors (Berkenbosch). A rise in CO2 tension not only acts as a stimulus to breathing; it has many other effects, e.g. changes in cerebral perfusion and in the
acid-base balance of blood, cerebrospinal fluid and brain tissue, each with its own time
constant. Thus the CO2 response is not exclusively dependent on the sensitivity of the
respiratory system to carbon dioxide. Sensitivity to CO2 is assessed by altering the CO2
tension of the breathing gas. The alteration
is measured from the end-expiratory CO2
.
tension, the effect on ventilation (V) being an estimate of the CO2 sensitivity. The following methods are available:
- In the steady-state method, the inspiratory CO2 tension is raised step-wise; during
each step the measurements are carried out after steady state is attained. This method
is very time consuming and not recommended for routine clinical investigations.
- The single-breath test comprises one single inspiration of a gas mixture with a high
CO2 tension, bringing about a rapid, transient rise in PCO2. This test is used to differentiate between the rapid response of the peripheral sensors and the slow reaction
of the central sensors.
The rebreathing method is used most (Read) (see figure). The subject breathes for 4-6
minutes into a 5 litre bag containing a mixture of 7% carbon dioxide and 93% oxygen.
Within a short time (15 seconds) CO2 equilibrium is attained between the blood, the
gases in the lung and the gases in the bag. Thereafter, the PCO2 in the system rises by
.
about 0.8 kPa/min (6 mmHg/min), the ventilation (V) increasing linearly with PCO2
.
(Fowler and Campbell) and the slope of the V-PCO2 curve being a measure of the
respiratory sensitivity to carbon dioxide. In the rebreathing method the body itself is the
source of the rise in CO2 (“endogenous CO2 loading”). In brain tissue, the CO2 source is
in the immediate vicinity of the central chemosensors, the CO2 gradients being relatively
small. This method has the further advantage of CO2 transport being negligible during
measurement, all changes occurring virtually simultaneously. In normal circumstances
the ventilation is a good estimate of central respiratory activity, although mechanical
disturbances of breathing can make interpretation of the CO2 response more difficult.
The normal variations in sensitivity to carbon dioxide are considerable: ventilation
sometimes responds by increasing the tidal volume and sometimes by increasing the
breathing frequency. In young adults, CO2 sensitivity varies from 15 to 40 L·min-1·kPa-1
(2 to 5 L·min-1·mHg-1) (Eger, Kronenberg, Hirshman), mainly as the result of differences
in tidal volume. Regarding disturbances in sensitivity to CO2, the following should be
noted:
- Patients with chronic obstructive lung disease often show an abnormally low CO2 sensitivity,
when this is estimated by ventilatory response (see 11.24). In most cases the reduced response
of ventilation indicates mechanical impairment of breathing
- Opiates and barbiturates reduce sensitivity to CO2.
- Reduced sensitivity to CO2 indicates an abnormally high tendency towards hypoventilation
(obesity, sleep, hyperoxia) (Dempsey).
- Disturbances in the acid-base balance affect the sensitivity to CO2 (see 11.17).
References on next page.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
References
Berger AJ, Mitchell PA, Severinghaus JW. New Engl J
Med 1977; 297: 194.
Berkenbosch A, et al. Respir Physiol 1979; 37: 381.
Dempsey JA. Chest 1976; 70 (suppl.): 114.
Eger EI, Kellogg RH, Mines AH, et al. J Appl Physiol
1968; 24: 607.
Fencl V. Chest 1976; 70 (suppl.): 113.
Fowle ASE, Campbell EJM. Clin Sci 1964; 27: 41.
Hirshman C, McCullough RE, Well JV. J Appl Physiol
1975; 38: 1095.
Kronenberg R, Hamilton FN, Gabel R, et al. Respir
Physiol 1972; 16: 109.
Read DJC, Leigh H. J Appl Physiol 1967; 23: 53.
Read DJC. Austr Ann Med 1966; 16: 20.
Rebuck AS. Chest 1976; 70 (suppl.): 118.
Rebuck AS, Read J. Clin Sci 1971; 31: 14.
Saunders KB. Clinical Physiology of the Lung. Blackwell, Oxford, 1977.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.16 Measurement of oxygen sensitivity
The sensitivity of the respiratory system to oxygen depends on the properties of the
chemosensors in the carotid body and on the effect of oxygen on the central regulation
of breathing. Hypoxia brings about a depression of the respiratory centres and affects
the blood flow, the cell metabolism, and the condition of the peripheral chemosensors.
For this reason, sensitivity to oxygen should be measured under accurately determined
conditions and at constant carbon dioxide tension (isocapnia). The following methods
are available:
- The steady state method comprises a step-wise decrease of oxygen tension in the
inspired gas: after each step-wise change the relationship between ventilation and
oxygen tension is determined under steady state conditions. This method is time
consuming and is not recommended for routine clinical investigation.
- The single breath hypoxia test comprises a single deep breath of a gas with a low oxygen concentration or even pure nitrogen. The advantage is that measurement takes
place before complicating mechanisms can come into play, but the results are difficult
to interpret.
- The progressive hypoxia method (Cormack) (see figure). The subject breathes into a
closed spirometer system, uptake of oxygen causing the oxygen tension to fall from
16 kPa (120 mmHg) to 5.3 kPa (40 mmHg) over a period of 3-4 minutes. During this
period, 6-8 arterial blood samples are taken and, using these as a guide, the arterial
CO2 tension is kept constant with the help of the CO2 shunt in the spirometer circuit.
The relationship between ventilation and arterial oxygen tension is thus obtained at
constant Pa,CO2. This method is clinically feasible, but investigation with a hypoxic
gas mixture requires many precautions. The results reflect the oxygen sensitivity of
the body as a whole and are thus dependent on the oxygen sensitivity of the peripheral chemosensors, the central hypoxic depression, and the above complicating factors.
The relationship between the hypoxic stimulus (reduced
. oxygen tension in the arterial
blood) and the concomitant change in ventilation (V) is a curve, so it cannot be represented by one single index. However, the relationship between ventilation and oxygen
saturation of haemoglobin (Sa,O2) is linear. The transposition of oxygen tension to
impulse frequency (ventilatory drive) in the carotid body happens to correspond to the
oxyhaemoglobin dissociation in the blood: Sa,O2 is, however, not the stimulus of the
chemosensors. By using a pulse oximeter to measure Sp,O2, or by measuring Pa,O2 transcutaneously, the sensitivity to oxygen (hypoxia-sensitivity) can be determined without
taking blood. If ventilation is plotted against Pa,O2, the oxygen sensitivity is derived from
the increase in ventilation when the Pa,O2 falls from 20 to 5.3
. kPa (150 to 40 mmHg). As
the measurement involves the linear relationship between V and Sp,O2, the slope of the
oxygen-response line is a measure of sensitivity to oxygen.
The wide range of the reference values is due to differences in method and to anthropometric and hereditary factors. The oxygen sensitivity is relatively low in the physically
fit, increasing with increase in metabolism (work, hyperthermia, thyrotoxicosis). Sensi-
tivity to oxygen diminishes with age.
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J Med 1977; 297: 194.
Cormack RS, Cunningham DJC, Gee JBL. Quart J Exp Physiol 1957; 42: 303.
Kronenberg R, Hamilton FN, Gabel IR, et al. Respir Physiol 1972; 16: 109.
Lourenço RV. Chest 1976; 70 (suppl.): 109.
Lloyd BB, Jukes MGM, Cunningham DJC. Quart J Exp Physiol 1958; 43: 214.
Milic-Emili J, Grunstein MM. Chest 1976; 70 (suppl.): 131.
Rebuck AS, Kangalee M, Pengelly LD, Campbell EJM. J Appl Physiol 1973; 35: 173.
Riedstra JW, Berkenbosch A. Acta Physiol Pharmacol Neerl 1963; 12: 105.
Severinghaus JW, Ozanne G, Massuda Y. Chest 1976; 70 (suppl.): 121.
Severinghaus JW, Bainton CR, Carcelen A. Respir Physiol 1966; 1: 308.
Saunders KB. Clinical Physiology of the Lung. Blackwell, Oxford, 1977.
Well JV, Zwillich CW. Chest 1976; 70 (suppl.): 124.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.17 Regulation of acid-base balance
Regulation of the acid-base balance is closely linked to the exchange of CO2, HCO3- and
H+ between blood and brain compartments (see 11.4). In the following we consider the
cerebospinal fluid (CSF) as representative of the extracellular brain fluid, wherein the
central chemosensors are located.
Respiratory acidosis
Acute disorder. The PCO2 in the blood rises, and allied with it the HCO3- and cH+. Carbon dioxide easily diffuses across the blood- brain barrier, so the PCO2 in the CSF rises
to the same extent. HCO3- crosses the blood-brain barrier more slowly. As the CSF is
only weakly buffered, its cH+ rises above that of the blood.
Compensation. As a result of renal compensation the HCO3- concentration in the blood
rises, and the cH+ again approaches normal. The cH+ in the CSF rises as a result of tissue
buffering and transfer across the blood-brain barrier. This causes a considerable drop in
the cH+ in the CSF: the acidosis is thus partially compensated for.
Sudden recovery. If the cause of the respiratory acidosis (hypoventilation) is suddenly
removed and the PCO2 rapidly returns to normal, compensatory metabolic alkalosis
remains, especially in the CSF, because HCO3- crosses the blood-brain barrier comparatively slowly. This CSF alkalosis leads to disturbances in brain function; a slow recovery
phase is therefore vitally important.
and resulting from slow passage across the blood-brain barrier, the cH+ in the CSF again rises to
normal values, and the HCO3- falls.
Sudden recovery. If the non-respiratory disturbance is suddenly removed or corrected therapeutically (e.g. by bicarbonate infusion) the cH+ of the blood returns to normal, and the H+ stimulation
of the peripheral chemosensors decreases. This rapidly normalises the PCO2 in blood and CSF,
resulting in transient alkalosis in the CSF. The selective permeability of the blood-brain barrier to
CO2 means that the effect of sudden recovery from non-respiratory acidosis on the CSF is less than
that in recovery from respiratory acidosis.
Continued on next page.
Respiratory alkalosis
Acute disorder. The PCO2 in the blood falls, and with it the HCO3- and cH+. Carbon
dioxide readily diffuses across the blood-brain barrier, so the PCO2 in the CSF falls to the
same extent. This does not apply to HCO3-. For this reason the cH+ in the cerebrospinal
fluid is below that of the blood.
Compensation. The concentration of HCO3- in the blood falls as a result of renal excretion. The cH+ thus approaches normal values again. The HCO3- in the CSF falls as a
result of in situ production of lactate and by (active) transport across the blood-brain
barrier. The cH+ in the CSF thus rises.
Sudden recovery. If the respiratory disturbance (hyperventilation) is suddenly removed
and the PCO2 quickly reaches normal values, the HCO3- in the CSF cannot follow the
rapid PCO2 change, and transient CSF acidosis ensues. Hyperventilation continues until
the HCO3- in the CSF is normal.
Non-respiratory acidosis
Acute disorder. Initially, an acute rise in the cH+ of the blood is only associated with a
fall in its HCO3-. Because of the low permeability of the blood-brain barrier to H+ and
HCO3-, the CSF values initially remain normal.
Compensation. The increased cH+ stimulates the peripheral chemosensors, causing an
increase in ventilation and resulting in a drop in PCO2 in the blood and CSF. This may
cause the cH+ in the CSF to fall below normal values. At the same time another, slower,
compensation process takes place at the central level: via cell metabolism in the brain
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
Non-respiratory alkalosis
Acute disorder. The drop in cH+ in the blood is initially associated with only a slight rise
in HCO3-. Because of the low permeability of the blood-brain barrier to H+ and HCO3--,
the CSF values initially remain normal.
Compensation. The low cH+ causes compensatory hypoventilation, resulting in increased
PCO2 in the blood and CSF. This may temporarily raise the cH+ in the-CSF. The composition of the CSF gradually changes, due to brain tissue metabolism and the passage of H+
and HCO3- across the blood-brain barrier, with the result that in the state of equilibrium
the cH+ of CSF attains normal values again.
Sudden recovery. If the non-respiratory disturbance is suddenly corrected, slight transient acidosis occurs in the CSF (after-effect). Because of the selective permeability of the
blood-brain barrier, the effect of non-respiratory alkalosis on the CSF is less than that of
respiratory alkalosis.
The difference in effect of respiratory and non-respiratory disturbances on the regulation
of breathing is due to the selective permeability of the blood-brain barrier. The cH+ in the
CSF is stabilized by the following factors:
- The endothelial cells of the blood-brain barrier generate a potential difference, as
a result of which the CSF is about +4 mV relative to the blood. This difference in
potential changes with pH, disturbances in acid-base balance in the CSF thus being
regulated.
- Changes in cerebral perfusion alter the PCO2 of the brain tissue and thus the pH of
the CSF.
- Changes in cerebral metabolism (e.g. production of acid metabolites in hypoxia)
affect the pH of the CSF.
- The cells of the brain generate HCO3-. Glial cells are especially rich in carbonic anhydrase.
References
Ahmad HR, Berndt J, Loeschcke HH. In: “Acid-base homeostasis of the brain extracellular fluid
and the respiratory control system (Loeschcke HH, editor). Georg Thieme, 1976.
Berger AJ, Mitchell RA, Severinghaus JW. New Engl J Med 1977; 297: 194.
Fencl V, Vale JR, Broch JA. J Appl Physiol 1969; 27: 67.
Leusen I. Physiol Rev 1972; 52: 1.
Mitchell RA, et al. J Appl Physiol 1965; 20: 443.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.18 Respiration and homoeostasis
Reference
Kao FF. An introduction to respiratory physiology. Excerpta Medica, Amsterdam, 1972.
Gas transport between the air and the tissues depends on the regulation of breathing,
circulation of blood, the transport capacity of the blood and the tissue metabolism. Regulation operates to maintain the values for oxygen, carbon dioxide and pH as constant
as possible (“chemostat”, Kao). Regulation of the blood gases and the pH of the arterial
blood is paramount; thus gas transport is governed by an arterial chemostat.
The extent of gas exchange (oxygen and carbon dioxide) and the formation of acid
metabolites depends on the metabolic activity in the tissues, especially the muscle tissue.
During heavy work, special demands are made on the regulating mechanism. At the
tissue level, the following mechanisms are available: the intracellular and extracellular
buffering of changes in pH, and the adaptation of the tissue circulation (microcirculation) to the altered circumstances.
The buffering capacity of the venous and arterial blood is the mechanism by which
homoeostasis is maintained, the function of the erythrocytes being central to this. There
is a powerful interaction between oxygen, carbon dioxide and hydrogen ion concentration: a change in oxygen combining power affects the carbon dioxide combining power
and pH, and vice versa (9.2 and 9.3). This interaction is instantaneous; longer term regulation mechanisms include changes in the composition of the blood and its buffering
capacity (haematocrit; haemoglobin content and organic phosphates; volume of circulating blood).
Adaptation of the circulation to metabolic needs is also very important: the immediate reflex mechanism is followed by the slow humoral regulating mechanism. Changes
in the rate of circulation of the blood result in changes in blood pressure and alterations in the distribution of blood throughout the body. Changes in the pulmonary and
cerebral circulation have the greatest effect, but those in the kidneys and muscles make a
strong contribution. The partial pressures of the gases in the blood leaving the lungs are
determined by the ventilation (external breathing). Gas exchange is not equally efficient
everywhere in the lung; this is due to differences in the regional distribution of the ventilation-perfusion and diffusion-perfusion ratios. The efficiency of alveolar gas exchange
determines the gas tensions in the arterial blood supplied to the tissues. The peripheral
chemosensors in the arterial bloodstream and the central chemosensors in the brain
tissue, which are indirectly linked with the arterial blood, perceive the gas tensions and
emit impulses to regulate the level of external respiration.
As far as central chemosensitivity is concerned, geometric relationships (blood vessels; brain tissue; cerebrospinal fluid; chemosensors) and buffer mechanisms play a part.
The fast component (seconds) of humoral regulation of breathing acts via the peripheral
chemosensors, and the slow component (minutes) via the central chemosensors. In
addition, nerve impulses from the muscle tissue, and possibly also from the circulation,
contribute to rapid adaptation of external gas exchange to the needs of the body.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.19 Ventilation during physical exertion
In the assessment of breathing during exertion, the transport of carbon dioxide (nCO2)
is usually taken as the measure of physical effort,
. because breathing is to a great extent
aimed at maintaining isocapnia. Ventilation (V) is used as an indirect measure of central
respiratory activity (see 11.10). During work, three phases are distinguished (see also 9.5):
During the initial phase, breathing is regulated via the proprioceptive sensors in the
working muscles, although cortical influences also play a part (anticipation, conditioned
response). Ventilation increases immediately after the onset of work and is very dependent on the way in which the exertion is started. Acute changes in blood circulation and
the arterial blood gas levels also contribute. In the initial phase, CO2 transport lags behind the nervous stimulation of ventilation, resulting in a temporary drop in the alveolar
PCO2.
The isocapnic phase begins about a minute after commencement of work. The metabolism is aerobic and there is no metabolic acidosis. The carbon dioxide tension is the
most important stimulus for the increase in ventilation. In moderate work und3r steady
state conditions the blood gas values and the acid-base balance scarcely deviate from the
normal values: some as yet obscure mechanism closely links ventilation with the increase
in metabolism. Ventilation increases
. almost proportional with gas transport up to about
70% of maximum oxygen uptake (VO2,max; aerobic capacity). In moderate work, an
increase in tidal volume predominates.
In the anaerobic phase, gas transport is out of phase with tissue metabolism, and metabolic acidosis occurs. In heavy physical work, metabolic acidosis is an additional stimulus
to breathing, the extra stimulus sometimes leading to tachypnoea and hypocapnia. This
extra increase in ventilation is largely due to stimulation of the peripheral chemosensors,
as found in examination of patients with the carotid body denervated.
. .
The ratio ΔV/ΔnCO2 is a measure of the ‘‘transport sensitivity” of the respiratory
system as a whole. In normal persons this quotient in the linear region is 0.56-0.67 (L/
mmol). This value is determined by the central respiratory activity as well as by the condition of the ventilatory apparatus. The hyperbolic relationship between ventilation and
carbon dioxide tension (see 11.13 and 11.14) implies that the CO2 transport sensitivity
of ventilation decreases as the PCO2 becomes greater (Wasserman). As the dead space
increases, ventilation becomes less efficient, and greater total ventilation is necessary to
meet the needs of CO2 transport; the ratio is abnormally high. External viscous loading
reduces the ventilatory response during work; external elastic loading has no effect on
the ratio but changes the ratio between VI and tI (see 11.12). Physical exertion during
hypoxaemia rapidly leads to anaerobic metabolism, with
production of lactic
. considerable
. curve is abnormally steep.
acid. Then, even with slight loading, the slope of the ΔV/Δn
CO
2
. .
Metabolic acidosis is associated with an increase in ΔV/ΔnCO2, whilst in metabolic alkalosis the ventilatory “transport sensitivity” is low as a result of increased carbon dioxide
transport capacity. Emphysema patients have a relatively strong ventilatory response to
work, whilst patients with chronic bronchitis have a normal or sub-normal ratio. A small
ventilatory response during work indicates an unfavourable prognosis.
References
Berger AJ, Mitchell RA, Severinghaus JW. New Engl
J Med 1977; 297: 194.
Jones NL. Chest 1976; 70 (suppl.): 169.
Kao FF. An introduction to respiratory physiology.
Excerpta Medica, Amsterdam, 1972.
Saunders KB. Clinical Physiology of the Lung. Blackwell, Oxford, 1977.
Wasserman K. New Engl J Med 1978; 298: 780.
Wasserman K. Chest 1976; 70 (suppl.): 173.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.20 Breathing pattern and ventilatory loading
The ventilatory system responds in various ways to mechanical loading (Derenne):
— Increase in the rigidity (elasticity and resistance) of the thoracic wall during contraction of the inspiratory muscles assist the ventilatory output to remain constant
under increasing loading;
— reflex increase in inspiratory muscle power through the muscle spindle reflex or
through an increase in central inspiratory activity and
— Reflex alteration in inspiratory switch-off time by stimulation of intrapulmonary
receptors, resulting in changes in the ratio. The respiratory system can be loaded in the
following ways:
— Elastic loading (A) by breathing in a small closed space. During the first breaths
the loading is taken up by the intrinsic mechanism of the chest wall (see above) and
by the vagus reflex (see 11.6). The chemosensors are then stimulated and the humoral component of the control of breathing goes into action. Elastic loading affects the
breathing pattern but not total ventilation.
— Viscous loading (B) by breathing through a narrow tube, thus increasing the
external flow resistance. This results in a reduction in ventilation; consequently the
humoral (chemosensitive) component of regulation comes into play. The greater
the ventilation during work, the less it is affected by resistive loading. However, the
breathing output is not a good measure of neural activity, because ventilation is altered
mechanically by the external resistance.
— Constant expiratory pressure loading by expiration through a water column of constant height. This loading results in an increase in lung volume which affects breathing
through the stretch sensors. However, these sensors gradually adapt to the new situation and the ventilatory response becomes smaller.
— Positive pressure breathing (D) by loading the spirometer bell with weights. This
results in an increase in the lung volume and stimulation of the stretch sensors.
Through the inflation reflex the breathing frequency decreases and respiration becomes deeper. The effect of positive pressure breathing on the pattern of breathing has
been studied in animal experiments by abolishing the innervation of one lung (Peset).
It has been established by the closing pressure method (see 11.10) that sudden external
flow loading is associated with an increase in central inspiratory activity. In normal
persons whose carbon dioxide tension is artificially raised to 7.3 kPa (55 mmHg),
external viscous loading causes an alteration similar to that found in patients during
acute asthmatic attacks (internal viscous loading) but clearly different from that in
patients with chronic obstructive lung disease. Control of breathing obviously changes
in long- lasting disturbances in pulmonary mechanics. It is not yet known how far
mechanical loading and chemical stimulation lead to comparable results, nor whether
mechanical loading is comparable in patients and normal persons.
References
Axen K, Sperber Haas S. J Appl Physiol REEP 1979; 46: 743.
Anthonisen NR. Chest 1976; 70 (suppl.): 168.
Baker JP, Frazier DT, Hanley M, Zechman FW. Respir Physiol 1979: 36: 337.
Derenne J.Ph, Macklem PT, Roussos CH. Am Rev Respir Dis 1978; 118: 373.
Koehler RC, Bishop B. J Appl Physiol REEP 1979; 46: 730.
Pengelly LD, Greener J, Bowmer I, Luterman A, Milic-Emili J. J Appl Physiol 1975; 38: 39.
Peset R, Heemstra H, Wildevuur C, et al. J Appl Physiol 1969; 27: 413.
Saunders KB. Clinical Physiology of the Lung. Blackwell, Oxford, 1977.
Zechman FW, Burki NK. Chest 1976; 70 (suppl.): 165.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.21 Breathing pattern and bronchial tone
References
Bouhuys A (editor). Airway dynamics. Charles C. Thomas, Springfield Illinois, 1970.
Szentiyanyi AJ. Allergy 1968; 42: 203.
The tonus of the bronchial muscles depends on the relative activities of the sympathetic
nervous system and the vagus nerve (the autonomous balance) (11.7). Impulses from
the higher brain centres (consciousness, emotions) and the internal environment of the
bronchial wall (serotonin, prostaglandin, histamine, bradykinin, slow-reacting substance
of anaphylaxis, blood gas levels, body temperature) determine the extent to which any
disturbance in autonomous balance shows itself as bronchoconstriction. Individual differences in bronchial sensitivity are due to this multifractional system (see also 11.7):
- Atropine causes bronchodilatation and prolongs the effect of sympathomimetic
drugs.
- Blood gas levels play a part: hypocapnia causes bronchoconstriction and hypercapnia
brings about bronchodilatation.
- Severing the vagus nerve (animal experiments) reduces bronchial muscle tone.
- Sympathomimetics cause bronchodilation without necessarily having any specific
effect on the bronchial muscles.
- Beta-receptor blocking substances (propranolol) cause bronchoconstriction.
- Abnormal stimulation of the J-sensors or irritant receptors causes bronchoconstriction (e.g. “exercise-“ or “antigen- induced” bronchial asthma).
- Inflation of the lung widens the airways mechanically, and in addition causes transient reflex bronchodilation in healthy persons.
These factors play an important part in obstructive lung disease. According to Szentivanyi (1968), bronchial hypersensitivity in asthmatic subjects is the result of persistent
incomplete beta-adrenergic blockade: Vagotonia prevails and bronchoconstriction
occurs via local mechanisms. The figure shows that the bronchial tone (bronchoconstriction) is the result of the mutual relationship of neural, humoral and bronchial factors. An
increase in bronchial tone (bronchoconstriction) has two effects:
- Narrowing of the airways is accompanied by an inspiratory shift of the resting
breathing level (see volume I: 3.13). The consequent increase in lung volume (inflation) causes mechanical dilatation of the airways and a reflex decrease in bronchial
tone. The stretch sensors are stimulated, resulting in an inflation reflex accompanied
by a slow deep breathing pattern.
- An increase in bronchial tone causes narrowing of the airways. Airway constriction is
associated with abnormally strong stimulation of the J-sensors. Bronchial tone is reinforced (positive feed back), and through the deflation reflex the breathing becomes
rapid and shallow. This effect opposes airway dilatation as a result of inflation of the
lung. The mechanical characteristics of the airways are determined by both factors.
The unstable pattern of breathing following an increase in bronchial tone (bronchial
constriction) is the result of the unstable balance between the inflation and the deflation
reflex, leading to ambivalence between slow deep breathing and quick shallow breathing.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.22 Regulation of breathing in bronchial asthma
An asthmatic attack is a complex event not limited to breathing but involving the entire
organism. During an attack, the patient governs his impairment to some extent by altering the type of breath-ing (volume and frequency; chest and abdominal breathing) or
the size of the lung (lung inflation). The autonomous respiratory rhythm generator is influenced by the cortical centres and is controlled by the ventilatory apparatus (neuronal
component) and the internal environment (humoral component). The humoral regulation (chemoregulation) serves to stabilize gas exchange in the tissues (homoeostasis, ventilatory drive), irrespective of the capability of the ventilatory apparatus. The immediate
state of gas exchange is monitored by the peripheral and central chemosensors; in cases
of acidosis, hypoxia and hypercapnia, central respiratory activity increases in order to
meet the ventilatory needs (see 11.11). The neural control serves the optimum functioning of the breathing apparatus. Its condition is monitored by stretch sensors in the lung
parenchyma and proprioceptive sensors in the muscles, the pattern of breathing (volume
and frequency; chest and abdominal breathing) thus being adjusted to requirements. In
serious disturbances of the ventilatory apparatus, an increase in central respiratory activity results in increased activity of the respiratory muscles, but this is not accompanied by
a corresponding increase in ventilation which is sufficient for the needs of the organism.
Further increase in central respiratory activity would lead to wasted work of breathing.
The course of an asthmatic attack is schematically analyzed against this background.
The following components are involved (see also 11.10): perception of breathing (P), central respiratory activity C, the respiratory muscles (M), ventilation (V) and gas transport
(G). From the ventilatory apparatus (mechanosensors), impulses ascend to the respiratory centre and to the centres of perception. In normal circumstances there is no conscious
perception of breathing (diagram 1). In an asthmatic attack, the following phases are
distinguished.
- Initial hyperventilation (2) is caused by increased stimulation of the mechanosensors
as a result of narrowing of the airways (see 11.21). The hyperventilation is usually
perceived by the patient himself. As there is more ventilation than required by the
tissues, the impulse frequency from the chemosensors is low.
- The initial hyperventilation rapidly leads to fatigue of the respiratory muscles. The
intensified central respiratory activity no longer results in increased gas exchange: the
hyperventilation changes to hypoventilation (3). In this transition the almost normal
arterial carbon dioxide tension masks the danger of ventilatory exhaustion (McFadden, Hugh-Jones).
The subsequent hypoventilation (4) is characterized by a greatly disturbed exchange of
gases (respiratory insufficiency), resulting in abnormal stimulation of the chemosensors.
Because of the mechanical disturbance of the ventilatory apparatus, the increased central
respiratory activity is not accompanied by gas transport sufficient to meet the body’s
needs. By hypoxia and, presumably also by adaptation, perception of the breathing dis-
turbance is reduced. If the respiratory muscles become exhausted, the situation rapidly deteriorates
and fatal respiratory insufficiency soon ensues.
As long as ventilatory reserves are available, there is a labile balance between optimal regulation of the type of breathing by means of mechanoreceptors and optimal control of the respiratory needs (central respiratory activity) by means of chemosensors. The breathing pattern is often
unstable and can be influenced voluntarily, in which case physiotherapy is advisable. If the limit of
ventilatory capacity is reached, the breathing pattern becomes monotonous and the patient can no
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
longer voluntarily regulate breathing. This is when to apply pharmacological stimulation
of the neuromuscular apparatus. If the ventilatory needs still cannot be met, artificial respiration is the only alternative.
References
Hugh-Jones P. Bull Europ Physiopath Resp (Nancy) 1978; 14: 233.
McFadden Jr. ER, Lyons FLA. New Engl J Med 1968; 278: 1072.
Szentivanyi A. J Allergy 1968; 42: 203.
Widdicombe JG. Arch Intern Med 1970; 126: 311.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.23 Regulation of breathing in chronic airflow limitation
Regulation of breathing in patients with chronic airflow limitation is explained by diagrams showing the various components of respiration: perception of breathing (P), central
respiratory activity C, respiratory muscles (M), ventilation (V) and gas transport (G).
From the ventilatory apparatus and gas transport, impulses ascend to the respiratory centre (see 11.22): the pattern of breathing is regulated by mechanosensors in the lungs and
respiratory muscles; the ventilatory requirements are adjusted by central and peripheral
chemosensors (diagram 1).
In obstructive lung disease, the primary disturbance is located in the ventilatory
apparatus: (diagram 2). This results in a disturbance of gas transport, which is detected by
the chemosensors. The respiratory centre is vigorously stimulated, resulting in increased
ventilation. The carbon dioxide tension is normalized, but not the oxygen tension due to
unequal ventilation/perfusion ratios (partial respiratory insufficiency: see 10.10). With the
aid of the mechanosensors in the lungs and the propriosensors in the respiratory muscles,
the pattern of ventilation is adapted to the changed conditions.
Severe obstructive lung disease leads to disturbances in gas transport which cannot
be corrected by increases in central respiratory activity. The requirement is greater than
the transport capabilities of the lung at the level of normal gas tensions. Satisfactory gas
transport can only be guaranteed by increasing both the carbon dioxide and the oxygen
gradients. This condition is called total respiratory insufficiency. When the disturbance
is very severe, the response of the respiratory centres to stimuli from the periphery is
reduced (hypoxic depression, and presumably adaptation to the changed conditions). It
is unknown to what extent hypoxia leads in the long term to depression of the cortical
influences on respiratory centres.
In mild obstructive lung disease the carbon dioxide sensitivity is usually normal, and
the carbon dioxide response curve lies within the normal range (see 11.14, 11.15). In
patients with severe chronic hypercapnia the carbon dioxide
sensitivity is low (Garrard),
.
seen by the shift to the right and the flat course of the V/PCO2 line. This is the result of
reduced sensitivity to CO2 of both the peripheral chemosensors and the centres in the medulla oblongata. Another factor is the increase in extracellular and the associated changes
in pH and buffering capacity (11.4).
The sensitivity to CO2 also depends on the adrenosympathetic activity, any reduction
in which is accompanied by a reduction in sensitivity to CO2. In chronic obstructive lung
disease the catecholamine metabolism may affect sensitivity to CO2 (Turino, Goldring).
Reduced sensitivity to carbon dioxide in hypercapnia and increased response to CO2 in
hypocapnia is a physiological adaptation mechanism which promotes metabolic homoeostasis. Note that in mechanical impairment of ventilation the ventilation response is not a
good indicator of central respiratory activity (see 11.10).
Regulation of metabolism is to ensure adequate carbon dioxide transport, and the
control of breathing is to ensure an adequate carbon dioxide tension. A reduction in
pulmonary CO2 transport caused by impairment of ventilation is compensated for by an
.
increase in carbon dioxide tension until the nCO2 again reaches the required value. The
.
non-linear relationship between ventilation and carbon dioxide tension at constant nCO2, together
with a reduced sensitivity to CO2, promotes metabolic homoeostasis. In this respect the bicarbonate ion concentration in the blood plays an important role (see 11.4).
References
Garrard CS, Lane DJ. Clin Sc 1979; 56: 215.
Goldring RM, Turino GM. Chest 1976; 70 (suppl.): 186.
Goldring RM, Heinemann HO, Turino GM. Am J Med Sc 1975; 269: 160.
Maranetra M, Payne MGF. Thorax 1974; 29: 578.
Turino GM, Goldring RM. Chest 1976; 77 (sippl.): 180.
Tammeling GJ, Quanjer PhH. Ned T Geneesk 1978; 112: 1968.
G.J. Tammeling and Ph.H. Quanjer
Contours of Breathing - Control of Breathing
11.24 Regulation of breathing in pulmonary fibrosis
Several aspects of lung function are disturbed in pulmonary fibrosis: elastic work of
breathing, lung volumes and to a minor extent airway resistance. These result in abnormalities of the breathing pattern and disturbances of gas exchange. The impaired breathing pattern is related to the excessive stimulation of the pulmonary mechanosensors. The
rigidity of the lung tissue, the stretch sensors are strongly stimulated during inspiration.
This results in a vagus reflex (inflation reflex) causing rapid, shallow breathing (see 11.6).
The mechanical impairment and the abnormally small lung volume affect the dynamics
of the airways: the irritant sensors are stimulated, resulting in shallow hyperpnoea, thus
further stimulating the stretch sensors. The overall result is shallow hyperventilation,
which reinforces the flow resistance in the airways, especially as interstitial fibrosis by no
means leaves the intrapulmonary airways unaffected. This accentuates the disturbances
in the ventilation/perfusion ratio.
Rapid shallow breathing is relatively advantageous in pulmonary fibrosis: because of
the small tidal volume, relatively little elastic work of breathing is required for inspiration
and because of the high breathing frequency, the best use is made of the patency of the
airways. The comparatively small elastic work, at the cost of a relatively high viscous effort, ensure that the total work of breathing is kept as small as possible (see figure). If the
vagus nerve is blocked, the perception of dyspnoea is reduced and breathing becomes
slower and deeper. Rapid shallow breathing accentuates existing unequal ventilation/
perfusion ratios. This causes disturbances in gas exchange: hypocapnia, often combined
with slight hypoxaemia. The hypocapnia indicates that ventilation is greater than is
required to satisfy the CO2 demands of the tissues. However, reduction of ventilation
reinforces the hypoxaemia. Evidently a compromise has to be made between work of
breathing, hypocapnia and hypoxaemia.
In diffuse pulmonary fibrosis the carbon dioxide response curve (see 11.13, 11.14)
is parallel to the normal curve shifted to the left (Lourenço) (see figure). The resting
ventilation is abnormally high, and associated with hypocapnia. This indicates increased
central respiratory activity as a result of stimulation of the pulmonary mechanosensors.
The parallel shift indicates that the sensitivity to CO2 of the respiratory system has not
deviated from normal.
References
Guz A, Widdicombe JG. Poumon Coeur 1968; 24: 1033.
Lourenço RV, et al. Am J Med 1965; 38: 199.
Tunno GM, Goldring RM. Chest 1976; 70 (suppl.): 180.
Widdcombe JG. Arch Intern Med 1970; 126: 311.
G.J. Tammeling and Ph.H. Quanjer