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Respiration: control of ventilation
RESPIRATORY PHYSIOLOGY
Respiration: control of ventilation James Waterhouse Iain Campbell
The control of ventilation involves control of: • the rhythmical process of inspiration and expiration • the overall rate of ventilation and gaseous exchange with the environment. Animal experiments show that the respiratory centres are in the pons and medulla, and the vagi are also involved. Figure 1 shows the breathing patterns after sectioning the brainstem at different levels, with the vagi remaining intact or sectioned. • The basic inspiratory–expiratory cycle originates from the medulla, but it is irregular in tidal volume and frequency. • A ‘smoothing’ of the respiratory cycle takes place in the pons. If the medulla and pons are intact, then respiration is normal, though voluntary influences, needed for speech and singing, are impossible. • Making a section above (rostral to) the medulla but below (caudal to) the nuclei parabrachialis (the pneumotaxic centre),
Respiratory patterns associated with sections of the brainstem at different levels, and vagotomy
Pons
Pneumotaxic centre Apneustic centre
Medulla
Inspiratory– expiratory centre
Vagi intact
Vagi cut
The horizontal dashed lines indicate normal functional residual capacity.
1
James Waterhouse is Professor of Biological Rhythms at the Research Institute for Sport and Exercise Sciences at Liverpool John Moores University. Iain Campbell is Consultant Anaesthetist at the University Hospitals of South Manchester NHS Trust and Visiting Professor of Human Physiology at Liverpool John Moores University.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10
357
© 2005 The Medicine Publishing Company Ltd
RESPIRATORY PHYSIOLOGY
causes inspiration to be prolonged; if the vagi are also sectioned, then apneusis develops – expiratory gasps for air from a position of exaggerated inspiration. Therefore, inspiration is normally inhibited by the pneumotaxic centre and the vagi.
Achieving total alveolar ventilation of 4 litres/min (required at rest) can be by an infinite combination of frequencies and depths of breaths. A low frequency of ventilation, such as 4 breaths/min, requires 1000 ml of air to be taken into the alveoli with each breath. Since about 150 ml of each breath is dead space, the tidal volume required is 1150 ml, about 13% of which is wasted. The rate of air flow required (1150 ml in 7.5 s of inspiration) is about 150 ml/s. The main problem is the large amount of work required to be done against recoil forces. Decreasing the size of each breath and increasing the frequency of ventilation requires less work to be performed against recoil forces. However, this change increases the effect of resistance. A high frequency of ventilation such as 25 breaths/min, requires 160 ml of air to be taken into the alveoli with each breath. For a tidal volume of 310 ml, about 48% would be wasted. The rate of air flow required (310 ml in 1.2 s of inspiration) is 258 ml/s. This more rapid air flow requires an increase in the work done against pulmonary resistance forces. The problem is exacerbated because there are more breaths per minute and an increased risk of turbulence in the airways. When air flow becomes turbulent rather than laminar, the pressure gradient required to move the air is increased. The total work done per minute equals the sum of work done against compliance and resistance forces. As the above analysis indicates, breaths that are too large or too rapid increase the respiratory effort required and the amount of work wasted. There is an intermediate frequency and depth of ventilation that requires a minimum of effort, and the natural frequency and depth – determined in part by the Hering–Breuer reflex acting via the vagi – are close to this.
Inspiratory–expiratory cycle Neurons in the medulla and pons discharge mainly during the inspiratory or expiratory phase of the respiratory cycle; they are often referred to as ‘inspiratory’ or ‘expiratory’ neurons, respectively. Neurons that fire during the inspiration–expiration and expiration–inspiration transitions are known as ‘switching’ neurons. Inspiratory neurons are most common in the dorsal medulla, expiratory neurons in the ventral medulla, and ‘switching’ neurons in the pons, but there is overlap between sites. The inspiratory and expiratory neurons send efferent impulses to the intercostal muscles and diaphragm, and the inspiratory neurons in particular receive inputs from the vagi and chemoreceptor areas (see below). The origin of the respiratory rhythm is not known in detail, but the following account covers the main principles. The respiratory cycle consists of coordinated phases of inspiration and expiration, and smooth transitions between the two. Inspiration causes the inspiratory cells to fire in unison, and the expiratory cells to be quiescent. This is achieved by the inspiratory cells exciting their inspiratory agonists and inhibiting their expiratory antagonists. Lung volume increases. Inspiration is terminated by several simultaneous influences. First, the excitability of the inspiratory cells falls (fatigue); second, the excitability of the quiescent expiratory cells rises; third, inhibitory inputs from stretch receptors in the bronchial tree of the expanding lungs (the Hering–Breuer reflex) travel to the inspiratory neurons via the vagi; fourth, inhibitory inputs reach the inspiratory cells from the pneumotaxic centre. This combination reaches a point when activity of the inspiratory neurons begins to decline. At this point, the expiratory neurons are released from their inhibition, and the system switches to the expiratory mode. Expiration takes place, often passively (see above), using the force of lung recoil. However, this does not negate the need for expiratory neurons. They are required firstly for rapid or deep expirations when expiratory muscle effort is necessary and secondly to reset the gamma-loops of the muscle spindle-extrafusal fibre system of the respiratory muscles, so that they do not oppose being stretched during expiration. Like inspiratory neurons, expiratory neurons also show self-re-excitation of their agonist neurons and inhibition of antagonistic neurons. The lungs decrease in volume. Expiration is terminated when the declining excitability of the expiratory neurons, the increasing excitability of the quiescent inspiratory neurons, and the falls of inhibitory impulses to the inspiratory neurons from the vagi and the pneumotaxic centre, all combine to switch the system back to the inspiratory mode. The cycle then starts again.
Whole-body chemoreceptor reflexes The basic respiratory cycle must be able to change in depth and frequency in order to keep oxygen and carbon dioxide levels normal, and to be able to deal with changes in metabolic demand (exercise), the partial pressure of ambient oxygen (altitude), and acid–base balance. Marked deviations from normal values lead to a deterioration in the body’s performance and even to death. Under normal circumstances (breathing atmospheric air at sea level), increasing the respiratory minute volume replenishes the alveolar air with atmospheric air that is higher in oxygen (about 150 mm Hg) and lower in carbon dioxide (less than 1 mm Hg). Since the blood is in equilibrium with the alveolar air, this raises the partial pressure of oxygen in the blood and lowers that of carbon dioxide. This does not significantly affect the amount of oxygen carried in the blood because the haemoglobin is already saturated, but it increases the amount of carbon dioxide blown off and decreases the amount of carbon dioxide carried in the blood (see Anaesthesia and Intensive Care Medicine 6:11: 366). Since carbon dioxde is in equilibrium with carbonic acid, the pH of the blood rises. Control of the respiratory gases in the blood is achieved by chemoreceptor reflexes. Considering the responses of the whole body, the most powerful stimulus to ventilation is asphyxia – the simultaneous presence of high carbon dioxide (and low pH) and low oxygen. This is the natural consequence of the respiration falling below that required to maintain normal values of the gases in blood.
The vagi and the control of respiratory work The vagi play an important role in terminating inspiration and thus in determining the tidal volume (Figure 1). The system is set so that the combination of frequency and depth of breathing at rest minimizes the work to be performed.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10
358
© 2005 The Medicine Publishing Company Ltd
RESPIRATORY PHYSIOLOGY
The effects of changing only one or two of the variables have been investigated experimentally (Figure 2). A rise of carbon dioxide in the body (hypercapnia), oxygen and pH being unchanged, is also a strong stimulus to ventilation, but not as strong as asphyxia. If the pH is lowered at the same time as carbon dioxide is raised, it exerts an independent (additive) effect, and the lines relating ventilation to carbon dioxide are parallel to one another. By contrast, if oxygen is lowered (hypoxia) in the presence of hypercapnia, then there is an interaction between the two stimuli (multiplicative effect), the hypoxia sensitizing the body to the hypercapnia, the lines relating ventilation to carbon dioxide diverging from one another. The body’s response to hypoxia is weak until it approaches dangerous levels (about 40 mm Hg). This appears to be partly because any increase in ventilation that hypoxia might produce also reduces respiratory drive by lowering carbon dioxide levels and raising the pH. If the levels of carbon dioxide and acid are kept at normal values during hypoxia, then the hypoxic response is greater, but it is still comparatively weak until oxygen tensions have fallen below about 50 mm Hg.
probably being involved, but the link between hypoxia and transmitter release is not understood. What is known is that anaemic hypoxia (due to a decreased amount of haemoglobin in the erythrocytes) is not a stimulus – the glomus cells monitor the blood plasma rather than the erythrocytes. The fact that the glomus cells are influenced by the oxygen supplied by the blood plasma rather than the oxygenated haemoglobin is less surprising when it is appreciated that, relative to its size, the carotid body receives the greatest blood flow of any organ in the body. The carotid body receives a sympathetic innervation. It is believed that, at the onset of exercise, an increase in sympathetic outflow constricts the blood vessels and this reduces the blood flow through the carotid body. This constriction produces a local stagnant hypoxia, and this contributes to the immediate increase in ventilation. How the carotid bodies respond to hypercapnia and increased acidity is unknown, though individual glomus cells appear to respond to all three stimuli. This gave rise in the 1930s to the unitary hypothesis, by which all stimuli acted by a common pathway, intracellular acidity. (For hypoxia, this is postulated to be via glycolysis and the production of lactic acid.) This hypothesis cannot be tested until simultaneous recordings have been made of intracellular acidity, oxygen and carbon dioxide from the same glomus cell and activity in the nerve arising from it.
Chemoreceptors The sensory limb of the chemoreflexes are the peripheral and central chemoreceptors. The peripheral chemoreceptors (aortic and carotid bodies) are wholly responsible for the reflex responses to hypoxia, but are sensitive to hypercapnia and lowered pH. The central chemoreceptors (on the floor of the fourth ventricle) are not sensitive to hypoxia, but are sensitive to the pH of the CSF.
Central chemoreceptors The central chemoreceptors comprise large neurons in the medulla, and are distinct from the respiratory centres described above. They monitor the CSF, particularly its pH. Owing to the blood–brain barrier, hydrogen ions from the blood cannot pass freely into the CSF, but changes in the partial pressure of carbon dioxide in the blood are reflected rapidly because there is no blood–brain barrier to this gas (nor to oxygen). The buffering capacity of the CSF is low; it contains no proteins. Accordingly, small changes in the partial pressure of carbon dioxide produce large changes in pH, and it is these changes that stimulate the chemoreceptors.
Carotid bodies Of the peripheral chemoreceptors, the carotid bodies have been studied more than the aortic bodies. The carotid bodies consist of round glomus cells surrounded by flattened sustentacular cells, and the sensory nerves abut the glomus cells. Hypoxia causes the nerves to increase their rate of firing, the release of dopamine
Relationship between ventilation and partial pressure of carbon dioxide Low pH
Integrating the receptor responses and the whole-body chemoreflexes How the responses of the chemoreceptor areas are integrated into the whole-body responses is unknown. It appears that the central chemoreceptors guard the CSF against changes in pH, and this protection extends to brain tissue, which is in equilibrium with the CSF. This stability of the brain tissue pH is vital if changes in excitability of the neurons (influenced by the level of free calcium which is, in turn, controlled by pH) are to be avoided. Oxygen levels are unimportant until they deviate markedly from normal. This is because there is a plateau at the top of the oxygen dissociation curve, and small falls in the partial pressure of oxygen at the lungs are without effect; blood leaving the lung continues to be saturated. It is only when the blood leaving the lung is no longer fully saturated with oxygen that its role as a transporter of this gas becomes compromised. This loss of saturation is not marked until the partial pressure of oxygen in blood has fallen below about 50 mm Hg, and this is the point at which the hypoxic drive begins to increase markedly. Considered in this way, the lack of sensitivity of the body to hypoxia is apparent rather than real, and this aspect of the chemoreceptor reflexes is suited to the needs of the body.
Additive effect
Ventilation
Normal pH
Low oxygen Normal oxygen Multiplicative effect
Partial pressure of carbon dioxide Effects due to simultaneous changes in oxygen (multiplicative) and pH (additive) are also shown. 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10
359
© 2005 The Medicine Publishing Company Ltd
Respiration: control of ventilation James Waterhouse Iain Campbell
The control of ventilation involves control of: • the rhythmical process of inspiration and expiration • the overall rate of ventilation and gaseous exchange with the environment. Animal experiments show that the respiratory centres are in the pons and medulla, and the vagi are also involved. Figure 1 shows the breathing patterns after sectioning the brainstem at different levels, with the vagi remaining intact or sectioned. • The basic inspiratory–expiratory cycle originates from the medulla, but it is irregular in tidal volume and frequency. • A ‘smoothing’ of the respiratory cycle takes place in the pons. If the medulla and pons are intact, then respiration is normal, though voluntary influences, needed for speech and singing, are impossible. • Making a section above (rostral to) the medulla but below (caudal to) the nuclei parabrachialis (the pneumotaxic centre),
Respiratory patterns associated with sections of the brainstem at different levels, and vagotomy
Pons
Pneumotaxic centre Apneustic centre
Medulla
Inspiratory– expiratory centre
Vagi intact
Vagi cut
The horizontal dashed lines indicate normal functional residual capacity.
1
James Waterhouse is Professor of Biological Rhythms at the Research Institute for Sport and Exercise Sciences at Liverpool John Moores University. Iain Campbell is Consultant Anaesthetist at the University Hospitals of South Manchester NHS Trust and Visiting Professor of Human Physiology at Liverpool John Moores University.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10
357
© 2005 The Medicine Publishing Company Ltd
RESPIRATORY PHYSIOLOGY
causes inspiration to be prolonged; if the vagi are also sectioned, then apneusis develops – expiratory gasps for air from a position of exaggerated inspiration. Therefore, inspiration is normally inhibited by the pneumotaxic centre and the vagi.
Achieving total alveolar ventilation of 4 litres/min (required at rest) can be by an infinite combination of frequencies and depths of breaths. A low frequency of ventilation, such as 4 breaths/min, requires 1000 ml of air to be taken into the alveoli with each breath. Since about 150 ml of each breath is dead space, the tidal volume required is 1150 ml, about 13% of which is wasted. The rate of air flow required (1150 ml in 7.5 s of inspiration) is about 150 ml/s. The main problem is the large amount of work required to be done against recoil forces. Decreasing the size of each breath and increasing the frequency of ventilation requires less work to be performed against recoil forces. However, this change increases the effect of resistance. A high frequency of ventilation such as 25 breaths/min, requires 160 ml of air to be taken into the alveoli with each breath. For a tidal volume of 310 ml, about 48% would be wasted. The rate of air flow required (310 ml in 1.2 s of inspiration) is 258 ml/s. This more rapid air flow requires an increase in the work done against pulmonary resistance forces. The problem is exacerbated because there are more breaths per minute and an increased risk of turbulence in the airways. When air flow becomes turbulent rather than laminar, the pressure gradient required to move the air is increased. The total work done per minute equals the sum of work done against compliance and resistance forces. As the above analysis indicates, breaths that are too large or too rapid increase the respiratory effort required and the amount of work wasted. There is an intermediate frequency and depth of ventilation that requires a minimum of effort, and the natural frequency and depth – determined in part by the Hering–Breuer reflex acting via the vagi – are close to this.
Inspiratory–expiratory cycle Neurons in the medulla and pons discharge mainly during the inspiratory or expiratory phase of the respiratory cycle; they are often referred to as ‘inspiratory’ or ‘expiratory’ neurons, respectively. Neurons that fire during the inspiration–expiration and expiration–inspiration transitions are known as ‘switching’ neurons. Inspiratory neurons are most common in the dorsal medulla, expiratory neurons in the ventral medulla, and ‘switching’ neurons in the pons, but there is overlap between sites. The inspiratory and expiratory neurons send efferent impulses to the intercostal muscles and diaphragm, and the inspiratory neurons in particular receive inputs from the vagi and chemoreceptor areas (see below). The origin of the respiratory rhythm is not known in detail, but the following account covers the main principles. The respiratory cycle consists of coordinated phases of inspiration and expiration, and smooth transitions between the two. Inspiration causes the inspiratory cells to fire in unison, and the expiratory cells to be quiescent. This is achieved by the inspiratory cells exciting their inspiratory agonists and inhibiting their expiratory antagonists. Lung volume increases. Inspiration is terminated by several simultaneous influences. First, the excitability of the inspiratory cells falls (fatigue); second, the excitability of the quiescent expiratory cells rises; third, inhibitory inputs from stretch receptors in the bronchial tree of the expanding lungs (the Hering–Breuer reflex) travel to the inspiratory neurons via the vagi; fourth, inhibitory inputs reach the inspiratory cells from the pneumotaxic centre. This combination reaches a point when activity of the inspiratory neurons begins to decline. At this point, the expiratory neurons are released from their inhibition, and the system switches to the expiratory mode. Expiration takes place, often passively (see above), using the force of lung recoil. However, this does not negate the need for expiratory neurons. They are required firstly for rapid or deep expirations when expiratory muscle effort is necessary and secondly to reset the gamma-loops of the muscle spindle-extrafusal fibre system of the respiratory muscles, so that they do not oppose being stretched during expiration. Like inspiratory neurons, expiratory neurons also show self-re-excitation of their agonist neurons and inhibition of antagonistic neurons. The lungs decrease in volume. Expiration is terminated when the declining excitability of the expiratory neurons, the increasing excitability of the quiescent inspiratory neurons, and the falls of inhibitory impulses to the inspiratory neurons from the vagi and the pneumotaxic centre, all combine to switch the system back to the inspiratory mode. The cycle then starts again.
Whole-body chemoreceptor reflexes The basic respiratory cycle must be able to change in depth and frequency in order to keep oxygen and carbon dioxide levels normal, and to be able to deal with changes in metabolic demand (exercise), the partial pressure of ambient oxygen (altitude), and acid–base balance. Marked deviations from normal values lead to a deterioration in the body’s performance and even to death. Under normal circumstances (breathing atmospheric air at sea level), increasing the respiratory minute volume replenishes the alveolar air with atmospheric air that is higher in oxygen (about 150 mm Hg) and lower in carbon dioxide (less than 1 mm Hg). Since the blood is in equilibrium with the alveolar air, this raises the partial pressure of oxygen in the blood and lowers that of carbon dioxide. This does not significantly affect the amount of oxygen carried in the blood because the haemoglobin is already saturated, but it increases the amount of carbon dioxide blown off and decreases the amount of carbon dioxide carried in the blood (see Anaesthesia and Intensive Care Medicine 6:11: 366). Since carbon dioxde is in equilibrium with carbonic acid, the pH of the blood rises. Control of the respiratory gases in the blood is achieved by chemoreceptor reflexes. Considering the responses of the whole body, the most powerful stimulus to ventilation is asphyxia – the simultaneous presence of high carbon dioxide (and low pH) and low oxygen. This is the natural consequence of the respiration falling below that required to maintain normal values of the gases in blood.
The vagi and the control of respiratory work The vagi play an important role in terminating inspiration and thus in determining the tidal volume (Figure 1). The system is set so that the combination of frequency and depth of breathing at rest minimizes the work to be performed.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10
358
© 2005 The Medicine Publishing Company Ltd
RESPIRATORY PHYSIOLOGY
The effects of changing only one or two of the variables have been investigated experimentally (Figure 2). A rise of carbon dioxide in the body (hypercapnia), oxygen and pH being unchanged, is also a strong stimulus to ventilation, but not as strong as asphyxia. If the pH is lowered at the same time as carbon dioxide is raised, it exerts an independent (additive) effect, and the lines relating ventilation to carbon dioxide are parallel to one another. By contrast, if oxygen is lowered (hypoxia) in the presence of hypercapnia, then there is an interaction between the two stimuli (multiplicative effect), the hypoxia sensitizing the body to the hypercapnia, the lines relating ventilation to carbon dioxide diverging from one another. The body’s response to hypoxia is weak until it approaches dangerous levels (about 40 mm Hg). This appears to be partly because any increase in ventilation that hypoxia might produce also reduces respiratory drive by lowering carbon dioxide levels and raising the pH. If the levels of carbon dioxide and acid are kept at normal values during hypoxia, then the hypoxic response is greater, but it is still comparatively weak until oxygen tensions have fallen below about 50 mm Hg.
probably being involved, but the link between hypoxia and transmitter release is not understood. What is known is that anaemic hypoxia (due to a decreased amount of haemoglobin in the erythrocytes) is not a stimulus – the glomus cells monitor the blood plasma rather than the erythrocytes. The fact that the glomus cells are influenced by the oxygen supplied by the blood plasma rather than the oxygenated haemoglobin is less surprising when it is appreciated that, relative to its size, the carotid body receives the greatest blood flow of any organ in the body. The carotid body receives a sympathetic innervation. It is believed that, at the onset of exercise, an increase in sympathetic outflow constricts the blood vessels and this reduces the blood flow through the carotid body. This constriction produces a local stagnant hypoxia, and this contributes to the immediate increase in ventilation. How the carotid bodies respond to hypercapnia and increased acidity is unknown, though individual glomus cells appear to respond to all three stimuli. This gave rise in the 1930s to the unitary hypothesis, by which all stimuli acted by a common pathway, intracellular acidity. (For hypoxia, this is postulated to be via glycolysis and the production of lactic acid.) This hypothesis cannot be tested until simultaneous recordings have been made of intracellular acidity, oxygen and carbon dioxide from the same glomus cell and activity in the nerve arising from it.
Chemoreceptors The sensory limb of the chemoreflexes are the peripheral and central chemoreceptors. The peripheral chemoreceptors (aortic and carotid bodies) are wholly responsible for the reflex responses to hypoxia, but are sensitive to hypercapnia and lowered pH. The central chemoreceptors (on the floor of the fourth ventricle) are not sensitive to hypoxia, but are sensitive to the pH of the CSF.
Central chemoreceptors The central chemoreceptors comprise large neurons in the medulla, and are distinct from the respiratory centres described above. They monitor the CSF, particularly its pH. Owing to the blood–brain barrier, hydrogen ions from the blood cannot pass freely into the CSF, but changes in the partial pressure of carbon dioxide in the blood are reflected rapidly because there is no blood–brain barrier to this gas (nor to oxygen). The buffering capacity of the CSF is low; it contains no proteins. Accordingly, small changes in the partial pressure of carbon dioxide produce large changes in pH, and it is these changes that stimulate the chemoreceptors.
Carotid bodies Of the peripheral chemoreceptors, the carotid bodies have been studied more than the aortic bodies. The carotid bodies consist of round glomus cells surrounded by flattened sustentacular cells, and the sensory nerves abut the glomus cells. Hypoxia causes the nerves to increase their rate of firing, the release of dopamine
Relationship between ventilation and partial pressure of carbon dioxide Low pH
Integrating the receptor responses and the whole-body chemoreflexes How the responses of the chemoreceptor areas are integrated into the whole-body responses is unknown. It appears that the central chemoreceptors guard the CSF against changes in pH, and this protection extends to brain tissue, which is in equilibrium with the CSF. This stability of the brain tissue pH is vital if changes in excitability of the neurons (influenced by the level of free calcium which is, in turn, controlled by pH) are to be avoided. Oxygen levels are unimportant until they deviate markedly from normal. This is because there is a plateau at the top of the oxygen dissociation curve, and small falls in the partial pressure of oxygen at the lungs are without effect; blood leaving the lung continues to be saturated. It is only when the blood leaving the lung is no longer fully saturated with oxygen that its role as a transporter of this gas becomes compromised. This loss of saturation is not marked until the partial pressure of oxygen in blood has fallen below about 50 mm Hg, and this is the point at which the hypoxic drive begins to increase markedly. Considered in this way, the lack of sensitivity of the body to hypoxia is apparent rather than real, and this aspect of the chemoreceptor reflexes is suited to the needs of the body.
Additive effect
Ventilation
Normal pH
Low oxygen Normal oxygen Multiplicative effect
Partial pressure of carbon dioxide Effects due to simultaneous changes in oxygen (multiplicative) and pH (additive) are also shown. 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:10
359
© 2005 The Medicine Publishing Company Ltd