Control of Respiration and its Factors | Humans | Biology

The normal rate or respiration in an adult is 14 to 18 per minute with a tidal volume of about 500 ml. The rate and depth of respiration (pulmonary ventilation per minute) is adjusted according to requirement of the body. For instance during muscular exercise metabolic activities are increased and the demand for oxygen by the working muscles is increased.

At the same time a large amount of carbon dioxide is produced by the muscles and it becomes necessary to eliminate it. Thus in muscular exercise the respiration is increased both in rate and depth. In fact the increase in minute ventilation is directly proportional to the magnitude of muscular exercise.

On the other hand, respiration is depressed during sleep when the metabolic rate is low. Since the rate and depth of respiration can be accurately adjusted to metabolic needs of the body there must be an efficient mechanism for its regulation.

Like other physiological functions of the body the act of respiration, too, is controlled by a special group of nerve cells in the brain stem, which constitutes the ‘respiratory centre’.

The activity of this centre is controlled by many factors which may be classified under two headings:

1. Nervous factors.

2. Chemical factors.

Respiratory Centre:

Respiratory centre consists of a widely scattered group of nerve cells in the reticular formation of the pons and medulla (Fig. 8.30) which may be divided into 3 major areas:

1. Pneumotaxic Area:

Located in the upper pons. It controls the activity of the two lower centres. Section at ‘M’ produces apneustic type of respiration characterised by prolonged inspiratory cramps. It has subsequently been established that section of vagal afferents together with section at ‘M’ is necessary for typical apneustic respiration.

2. Apneustic Area:

Located in the lower pons—so named because when isolated from the influence of pneumotaxic centre it leads to apneustic type of respiration mentioned above. Section at ‘N’ leads to gasping type of respiration from the medullary respiratory centre isolated from the influence of other parts of respiratory centre.

3. Medullary Area:

Section at ‘O’ produces stoppage of respiration be­cause the connection between the medullary respi­ratory centre and the motorneurones of the phrenic and intercostal nerves are severed.

Medullary respi­ratory centre located near the lower part of the floor of the fourth ventricle (Fig. 8.31) consists of two parts:

a. Inspiratory Centre – Ventromedially placed.

b. Expiratory Centre – Dorsolaterally placed.

The above conclusions were based on stimulation experiments. Subsequent careful studies with microelectrodes confirmed the existence of two sets of neurones (viz., inspiratory and expiratory) but they are comingled with each other, so that all the inspiratory or expiratory neurons are not collected together to form a ‘centre’ in the way it is usually understood. However for the sake of simplicity in description existence of such centres bilater­ally may be postutated.

1. It has been further postulated that inspiratory centre of one side has got connection with inspiratory cen­tre of opposite side. Same type of connection exists between the expiratory centres of two sides. So that stimulation of inspiratory centre of one side will have excite-inspiratory effect on the contralateral side. Same remark is true for expiratory centre.

2. Second postulation is that homolateral inspiratory and expiratory centres have got ‘to-and-fro’ connection and reciprocally inhibits the activity of each other, so that stimulation of the inspiratory centre is attended simultaneously with inhibito-expiratory effect, though the neurophysiological basis for this connection between inspiratory and expiratory centres has not been established.

3. The third postulation is that the medullary respiratory neurones have got an intrinsic rhythmicity of their own. If the medullary respiratory centre are isolated from impulses of higher parts by rostral transection ‘gasping’ type of respiration occurs (hence the name ‘gasping centre’). Further transection more caudally will cause complete isolation of the medullary centres which nevertheless exhibits some spontaneous rhythmic discharge at least in the inspiratory nerve calls.

The inspiratory centres, therefore, have got a basic rhythmicity of their own (c.f. cardiac muscle). This area, however, by itself is not capable of giving a normal smooth type of respiration. The exact mechanism by which normal rhythmic respiration is maintained is not yet properly understood. It is probable that normal respiration occurs due to co-ordinated activity of the 3 parts of the respiratory centres mentioned above.

Mechanism of Rhythmic Respiration (Fig. 8.32):

Inspiration commences by discharge of impulses from apneustic centre to the inspiratory centre. Apneustic centre at the same time sends impulses to the pneumotaxic centre of upper pons. This centre sends excitatory impulses to the expiratory centre which inhibits the inspiratory centre. The inspiratory centre at the same time receives inhibitory impulses from the vagal stretch afferents stimulated by lung inflation during inspiration.

Being influenced by the double negative feedback mechanism—the activity of the nerve cells of the inspiratory centre stops and expiration commences passively. The cycle is repeated automatically at the end of expiration because the vagal stretch afferents are no longer active and the reciprocal inhibition of inspiratory centre from expiratory centre comes to an end after the stoppage of activity of the expiratory centre (Fig. 8.33).

Reflex Effect on Activity of Abdominal Muscles:

In the standing position the abdominal muscles are active during expiration but in 3 resting person in supine position the abdominal muscles are inactive throughout the respiratory cycle.

i. During rapid breathing, e.g., exercise, the abdominal muscles become active during early expiration.

ii. Positive intrapulmonary pressure elicits reflex contraction of abdominal muscle. The response is abolished by vagotomy. Positive intrapulmonary pressure elicits contraction of abdominal muscles in a closed chest dog but fails to do so if the chest is opened though in this case the lung distension is greater.

The afferent fibres responsible for contraction of abdominal muscles, therefore, are separate from those concerned in Hering-Breure Reflex the reciprocal inhibition of inspiratory centre from expiratory centre comes to an end after the stoppage of activity of the expiratory centre (Fig. 8.34).

Role of Abdominal Muscles (Fig. 8.35):

During normal respiration the abdominal muscles are inactive.

They become active during:

i. Exercise and other conditions leading to hyperpnoea (increase in rate and depth of respiration).

ii. Positive pressure breathing (for example during anaesthesia when a pump is attached to an intra-tracheal tube).

iii. Diminution in blood volume in certain low pressure areas of circulatory system.

The atrial mechanoreceptors (and probably receptors in other parts of circulatory system) normally maintain reflexly the tone of the abdominal muscles. The afferent fibres run in the vagus and are separate from those concerned in Hering-Breuer reflexes. Centre for these reflexes is a group of nerve cells separate from those of respiratory centre and has been named as abdominal compression centre (ACC).

This centre is influenced by the adjoining respiratory centre in reflexes (1) and (2) and in reflexes from the Sino-aortic-zone, but is affected directly by reflexes from low pressure areas of cardio-vascular system. Amongst the latter the atrial mechanoreceptors have been extensively studied. Fall in pressure in the atria causes increased tonicity of abdominal muscles thereby diminishing the blood volume in the vessels of the abdomen and increasing the blood volume in the atria. Rise in atrial pressure has got opposite effect.

The existence of ACC (abdominal muscle tonus centre) separates from respiratory centre but acting in collaboration with it makes it probable that the activity of the abdominal muscles in respiration is in part determined by reflexes through this centre. This centre, like respiratory centre, is sensitive to PCO₂.

Besides respiration, the ACC also reflexly modifies the tone of the abdominal muscles in such a way that the intrathoracic blood volume remains unaltered and an effective cardiac output is maintained.

Nervous Control of Respiration:

The Hering-Breuer Reflexes:

These reflexes prevent over distension of the lungs during inspiration and collapse of the lungs during expi­ration. The former reflex is known as Hering-Breuer inflation reflex and the latter is Hering-Breuer deflation reflex.

1. Inflation Reflex:

The receptors for these reflexes are ‘stretch receptors’ located in the lungs, mainly the bronchi and bronchioles. They are stimulated during inspiration when the lungs become stretched. The afferent impulses travel in the vagi and are relayed in ‘tractus solitarius’ before they reach the respiratory centre where they exert an inspira­tion-inhibiting effect. The inspiration is thus cut off in time and expiration commences (Fig. 8.36).

Section of the vagi abolishes the inflation reflex when the inspiration gets unduly prolonged and the chest is held up in inspiratory position at a time when no air is entering the lungs.

2. Deflation Reflex:

The receptors may be described as compression respectors located probably in the alveolar septa. They are stim­ulated during expiration and reflexly inhibits expiration and reciprocally stimulates inspiration. The afferent fibres are carried in the vagi. The deflation is thus mediated by a separate set of receptors and carried by a separate set of fibres in the vagi.

It may be mentioned that during normal expiration the stretch receptors become unstretched resulting in cessation of inhibitory impulses to the inspiratory centre. Since this centre is tonically active, inspiration commences as soon as inspiration-inhibiting impulses resulting from lung inflation ceases.

The inspiration-exciting effect of ‘deflation reflex’ becomes obvious in condition, such as, pneumothorax, hydrothorax, etc. where the degree of collapse of the lungs is more severe and results in stimulation of the respiratory process.

The physiological effect of Hering-Breuer reflexes is to maintain the extent of lung inflation so that the tidal volume tends to fall within a useful range. Indirectly the respiration rate is also adjusted so as to maintain adequet level of pulmonary and alveolar ventilation.

Impulses from Ascending Tracts of the Spinal Cord (Fig. 8.37):

It has been mentioned that the respiratory centre consists of a specialised group of cells in the reticular formation. The cells of the reticular formation receive impulses from the collaterals of the ascending tracts. It is believed that those sensory impulses from different parts of the body play an important facilitatory role in maintaining normal respiration. In a patient with depressed respiratory centre respiration may be stimulated by peripheral stimulus of any kind, such as slapping the skin. In fact, it is the practice to slap the new-born baby to establish the first respiratory cycle of life.

Stimulation of any afferent nerve causes reflex alteration in breathing, pain fibres are specially potent in this respect, stimidation of cold fibres such as application of cold water on the face has got well-known excitatory effect on respiration. Heat receptors located on the skin and in the hypothalamus are stimulated by warm blood during exercise and fever and produce hyperventilation. Muscular proprioceptors send afferent impulses to the respiratory centre and markedly stimulate respiration during muscular exercise. Proprioceptors of the respiratory muscle profoundly modify the respiratory movement of the next cycle.

Rise in pressure in right atrium and the great veins reflexly augment respiration during muscular exercise and cardiac failure.

Glossopharyngeal nerve contains afferent fibres which inhibit respiration during second stage of deglutition.

Hiccough is due to reflex spasm of the diaphragm associated with spasm of the laryngeal muscles arising from irritation of sensory nerve endings of the gastrointestinal tract.

Stimulation of somatic sensory nerves of the nose inhibits respiration and may cause reflex sneezing.

Coughing is a reflex phenomenon caused by irritation of the mucous membrane of the respiratory tract. It is an important protective reflex in which the irritant material is got rid of from the respiratory tract. At the beginning of the act a deep inspiration is taken, the glottis is then closed and violent expiratory effort is made against a closed glottis causing great rise in intrathoracic pressure. The glottis is then opened suddenly causing expulsion of the ‘cough’—the droplets are ejected with the velocity of a jet plane.

Reflexes from Sino-Aortic Zone:

A sudden rise of pressure in this area causes reflex slowing in the rate and amplitude of breathing. If the pressure rise is considerable in experimental animals, apnoea may result (adrenaline apnoea). If the rise in blood pressure is maintained for some time an ‘escape’ occurs and respiration commences again. This is due to adaptation of the receptors and rise in Pco₂ during apnoea stimulating respiratory centre. Fall in blood pressure stimulates respiration reflexly through the chemoreceptors of the Sino-aortic zone.

The reflex slowing of respiration during the rise of blood pressure depresses the ‘pump’ effect on the abdominal venous reservoirs so that less blood enters the heart and cardiac output is also depressed. Fall of blood pressure is associated with hurried respiration so that more blood is pumped from the abdomen to the thorax which causes an increase of cardiac output. The important role played by abdominal muscles in these responses can be easily understood and is controlled by ‘abdominal compression centre’ under the influence of respiratory centre.

Distension of Pulmonary Vascular Bed:

In experiments where the pulmonary vascular bed was completely isolated but for its nerve supply—disten­sion of the vessels caused rapid shallow breathing.

This was abolished by vagotomy proving its reflex nature. This explains rapid shallow breathing in patients suffering from pulmonary congestion.

Chemical Control of Respiration:

The three most important chemical factors which affect respiration are:

1. CO₂ content of the blood or to be more precise tension of CO₂ (Pco₂) in the arterial blood.

2. OH of blood

3. O₂ tension (Po₂) of the arterial blood.

CO₂ and Respiration:

Haldane and Smith demonstrated the effect of rising concentration of CO₂ in inspired air on respiration by making a subject rebreathe his own expired air. They noticed that with an increase in concentration of CO₂ in the inspired air the pulmonary ventilation increased remarkably and that respiration increased both in rate and in depth.

Atmospheric air normally contains a negligible amount of CO₂ (0.03%). The concentration of CO₂ in the inspired air may be increased up to 1% without any noticeable effect on pulmonary ventilation (respiratory minute volume, RMV). If 4% of CO₂ is inhaled, the RMV is approximately doubled and the subject becomes conscious of his respiration.

At concentrations above 6% the cardiac and respiratory functions are depressed and subjective symptoms like confusion and headache occurs. In fact the RMV does not increase significantly when more than 10% CO₂ is inhaled. About 20% CO₂ in inspired air produce depression of respiration associated with convulsive seizures.

The RMV and alveolar Pco₂ (P_A,co₂) are interdependent upon each other and further P_A,co₂ increases as the CO₂ of the inspired air increases. In the experiments of Haldane and Smith the alveolar Pco₂ was increased gradually by making the subject’s rebreathe his own expired air over a period of time. It was demonstrated that within the physiological range increase in P_A,co₂, is attended with a linear increase in the RMV.

The purpose of this respiratory stimulant effect of CO₂ will be obvious by looking at the simple model shown in Fig. 8.38. ‘A’ is a compressible bulb represents the lungs with a tube attached to it (the airways). Fig. 8.38 shows that, A’ is filled with some quantity of smoke (CO₂).

There is also a device fitted at ‘A’ through which smoke can be injected. It will be un­derstood that if more and more smoke is injected into the bulb and at the same time the bulb is pumped more and more vigorously the amount of smoke injected in will be equal to the amount of smoke ejected out of the bulb and the concentration of smoke within the bulb will not rise, provided the amount of smoke injected is not excessive.

Increased P_A,co₂, stimulates respiration and thereby drives out increasing amount of CO₂ from the lungs with each expiration so that an attempt is made to keep the P_A,co₂ at its resting level. This compensation, of course fails when the concentration of CO₂ in the inspired air exceeds 5%. Table 8.13 illustrates the point.

Site of Action of CO₂:

The powerful stimulant action of CO₂ on respiration has been well established.

CO₂-sensitive cells (chemoreceptors) are located in two places:

i. Centrally in the medulla.

ii. Peripherally in the carotid and aortic bodies.

Central Chemoreceptors:

These cells are located bilaterally on the ventral aspect of the medulla and are placed superficially anterior to the point of entry of the glossopharyngeal and vagus nerves. They are highly sensitive to CO₂ change and to change in pH of the blood and also of cerebrospinal fluid (CSF). Rise in Pco₂ or fall in pH stimulates these chemoreceptors primarily which again stimulates secondarily the cells of the respiratory centre increasing the volume and frequently of respiration.

In an elaborate series of experiments Pappenheimer and his co-workers perfused the ventriculo-cisternal systems of goats with HCO₃^– solution of different concentration and measured their ventilatory response to CO₂. They concluded that CO₂ acts as a respiratory stimulus by increasing [H⁺] in the interstitial fluid of the chemoreceptor cells scattered in the vicinity of the capillaries of bulbar reticular formation. These cells are not placed superficially and do not come in direct contact with the CSF.

Mode of Action:

CO₂ by itself has little direct stimulant action on respiration. The most po­tent source of stimulation is rise in TP concen­tration which occurs whenever there is arise in Pco₂ according to the equation CO₂ + H₂O ↔ H⁺+ HCO₃^–. H⁺ cannot diffuse easily from blood to the brain or to CSF but CO₂ can diffuse freely in either direction.

A rise in H⁺ concentration of the blood therefore will have a delayed access to the chemoreceptor cells whereas a rise in CO₂ concentration of the blood will be followed very soon by rise in CO₂ concentration of the CSF and tissue fluid in the brain. The H⁺ liberated in CSF by dissociation of H₂CO₃^– will have immediate and direct access to the medullary chemorecep­tor stimulation of respiration.

The H⁺ liberated in brain tissues will be ‘buffered’ in the first instance by the acid-base buffers of the brain and its ac­tion on the chemoreceptors will consequently be delayed (Fig. 8.39). It may be noted that there is no significant amount of ‘buffers’ in the CSF.

The initial-stimulating effect of CO₂ on respiration declines after a few minutes. This is due to the fact that HCO₃^– is transported activity from the blood to the CSF and thus the H⁺ of the CSF is neutralised to a considerable extent. This explains the diminution of stimulant effect on respiration of CO₂ which is prompt at the onset but declines to about one-fifth of the original effect after about 2 days.

From the quantitative point of view CO₂ is more potent a respiratory stimulant than H⁺ and further the action of both these factors is very conspicuous in the neighbourhood of their normal value. Thus the respiratory stimulant effect of CO₂ is most prominent in the neighbourhood of Pco₂ range of 40 to 45 mm Hg and that of H⁺ in the range of pH 7.45 to 7.35.

Peripheral Chemoreceptors:

Chemoreceptor cells are located in carotid and aortic bodies and reflexly stimulate respiration when the concentra­tion of CO₂ of the blood flowing through them is increased. Arguments have been raised regarding the relative importance of the central versus peripheral chemoreceptors in normal respiratory drive.

It appears that the central receptors are more important in this respect—the peripheral receptors playing a secondary supporting role in conditions of emergency. In animals after chronic denervation of the carotid and aortic bodies the resting minute volume (RMV) of respiration falls to 80% of normal and consequently the arterial Pco₂ rises by 10 mmHg.

It is, therefore, reasonable to conclude that 80% of the resting respiratory drive of respiration is due to central chemoreceptors and 20% due to peripheral chemoreceptors.

Oxygen Tension and Breathing:

This has been studied by making the subject breath O₂ and N₂ mixture containing different proportion of oxygen. Normal atmospheric air contains 20.93% of O₂. The amount of oxygen in the inspired gas mixture can be reduced to about 12% in many individuals without any appreciable change in ventilation.

However at levels of 10% of O₂ in the inspired air the respiration is stimulated with simultaneous reduction of P_A,co₂ as a result of hyperventilation. The low P_A,co₂ has a depressant action on respiration. It is clear, therefore, that respiration-stimulating effect of O₂ lack will be enhanced if suitable measures are taken to prevent the fall of p_A,co₂ by adding appropriate amount of CO₂ to the inspired air.

Further a subject breathing low concentration of O₂ will have a low P_A,o₂, a condition analogous to the situation of a subject at high altitude where the low P_A,o₂ is due to fall in barometric pressure. It can be calculated that the P_A,co₂ of a subject at 5.5 km (18,000 feet) is the same as that of a subject at sea-level breathing 10.5% of O₂. In both the resultant hyperventilation will lead to fall in P_A,co₂ and alkalosis, which is corrected later by the kidneys. It is known that fall in P_A,co₂ by 4 mm Hg causes apnoea and alkalosis depresses respiration.

The respiration under these conditions is maintained entirely by O₂ lack or a re-adjustment of sensitivity of respiratory centre to CO₂. In acute exposure to high altitude respiratory drive is maintained by O₂ lack only whereas in persons residing at high altitude for some time the respiratory centre becomes sensitive to low Pco₂.

Mode of Action of Oxygen Lack:

The respiration stimulating effect of O₂ lack is seen only in intact animals. In an animal with denervated carotid sinus O₂ lack will depress breathing. It has been proved by various workers and is a universally accepted fact that direct action of O₂ lack on respiratory centre is depression of respiration—the respiration-stimulating effect of O₂ lack is a reflex one through the Sino-aortic chemoreceptors.

The discharge of impulses from the chemoreceptor cells increases with the fall in oxygen tension of the arterial blood—the maximum effect is observed between arterial PO₂ of 60 mmHg and 30 mmHg. This is range in which percentage saturation of blood with oxygen falls almost perpendicularly (dissociation curve) and consciousness is lost very soon.

The carotid and aortic bodies are most highly vascular structure in the body. Consequently, the arterio-venous oxygen content difference is very low. In hypotension with blood pressure near about 60 mmHg the blood flow through these structures becomes very slow and sluggish and the arterio-venous O₂ content difference becomes high indicating low Po₂ within the chemoreceptor cells. Under these conditions there occurs reflex stimulation of respiration (and also vasoconstriction) which tends to restore the blood pressure to near normal value.

In conclusion it may be said that under normal conditions the level of pulmonary ventilation is controlled by three chemical agencies:

i. Rise in arterial Pco₂.

ii. Fall in arterial Po₂.

iii. Increase in arterial cH.

Any one of these factors may play a major role in driving respiration. It seems that above a certain range (approximately 75 mmHg Po₂ of inspired air) O₂ lack has no effect on respiration, similarly below a certain range (approximately 33 mmHg Pco₂)— CO₂ has no effect on respiration.

Under ordinary circumstances the effect of above three factors are additive but one of three factors is enough to augment ventilation in the absence of other two. For example in metabolic acidosis there is great increase in H⁺ concentration of the blood, the PO₂ being normal and PCO₂ below normal. However, the RMV is greatly augmented in this condition.