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Respiration: control of ventilation
PHYSIOLOGY
Respiration: control of ventilation
Learning objectives After reading this article you should be able to describe the: C neural arrangement that produces the basic respiratory rhythm C short-term control of blood carbon dioxide, oxygen, pH and combined changes of these variables C role of the peripheral chemoreceptors in controlling these variables, and of the central chemoreceptors when chronic hypoxia is present (at altitude) C role of neural influences in regulating the chemoreceptor reflexes, as well as in regulating the rate and depth of ventilation
Emrys Kirkman
Abstract Rhythmic ventilation is an automatic process controlled by the central nervous system. Groups of cells in the brainstem, predominantly the ventral and dorsal respiratory groups, are responsible for generating basic respiratory rhythm. This basic rhythm is subject to modulation by both conscious and reflex actions. In normal individuals the respiratory minute volume is set to closely regulate arterial carbon dioxide tension (PaCO2) at approximately 5.3 kPa, predominantly via a negative feedback reflex involving the central chemoreceptors. A separate group of chemoreceptors, the arterial chemoreceptors, are responsible for initiating the increased ventilatory response to counter arterial hypoxia, but a brisk response is not seen until PaO2 levels fall to approximately 8.0 kPa from the normal 13.3 kPa. Combined hypercarbia and hypoxia (asphyxia) is a very powerful stimulus to breathe as the two inputs interact in a synergistic manner. The chemoreceptor reflexes can be modified when the need arises (e.g. blockade of the respiratory part of the arterial chemoreflex by the trigeminal reflex as part of the diving response). Other reflexes such as the HeringeBreuer reflex contribute to setting the balance between tidal volume and respiratory rate to attain a given minute volume, although this reflex does not appear to play a major role in humans at resting tidal volumes. Superimposed on this ‘tonic’ control, additional protective reflexes (e.g. from receptors in the upper airways) are recruited to protect the lungs and airways with responses such as coughs and sneezes when required.
Origin of respiratory rhythm
taken many years and is still continuing. Earlier ideas, based on experiments where gross changes in patterns of breathing were seen following transactions and focal lesions in the brainstem led to the concept of multiple respiratory ‘centres’ (e.g. apneustic and pneumotaxic centres), which interacted to provide respiratory rhythm. This type of concept is now outdated and the altered pattern of breathing seen in these experiments is now viewed as the result of general damage rather than disconnecting specific centres. Control of ventilation is affected by clusters of neurones that are grouped in several distinct areas of the brainstem. Two such areas in the medulla are called the ventral respiratory group (VRG) and the dorsal respiratory group (DRG). Current thinking is that rhythm generation is the domain of a group of tightly clustered neurones in the VRG (specifically in the rostral ventrolateral medulla) called the pre-Botzinger complex (PBC). Although the PBC is itself a complex area containing a heterogeneous population of neurones, the PBC neurones thought to be responsible for respiratory rhythmogenesis are all interneurones in the sense that they have no axons projecting out of the brainstem. PBC neurones then ‘drive’ groups of inspiratory neurones. A strong piece of evidence suggesting that the PBC neurones are indeed the respiratory rhythm generator is the finding that a small focal lesion in this area produces an immediate fatal apnoea. In addition, the VRG is viewed as being more important than the DRG in the generation of respiratory rhythm because the DRG has not been found in a number of species. The inspiratory neurones have a major output into the spinal cord and relevant cranial nuclei to influence the activity of relevant motorneurones. Other areas in the brain that influence the VRG (and DRG) are thought to modify the pattern of breathing, especially depth. One of these areas is the apneustic centre or Botzinger complex (Kolliker-fuse area) of the pons. Experimental evidence suggests that disruption of any of these areas (other than the PBC) will modify the depth or pattern of breathing, but will not abolish rhythmogenesis.
The search for the area(s) of the brain and underlying mechanisms responsible for setting the basic respiratory rhythm has
Control of carbon dioxide tension in arterial blood
Keywords Aortic bodies; arterial chemoreceptors; carotid bodies; central chemoreceptors; diving response; HeringeBreuer reflex; respiratory rhythm Royal College of Anaesthetists CPD Matrix: 1A01
Ventilation is an automatic process that is controlled by the central nervous system. The brainstem is a key area responsible for the basic respiratory rhythm. This in turn is modulated by a number of influences ranging from conscious alterations (originating form ‘higher centres’), tonic reflexes such as the chemoreceptor reflexes regulating carbon dioxide levels of the blood and preventing dangerous hypoxia to episodic reflexes such as coughing and sneezing.
Carbon dioxide tension in arterial blood (PaCO2) is very closely regulated around a set point (5.3 kPa or 40 mmHg in a healthy individual) by a negative feedback system. A rise in PaCO2 stimulates a reflex increase in ventilation, excreting excess CO2 and returning PaCO2 to the set point. Conversely, a fall in CO2 attenuates tonic respiratory drive, resulting in a fall in ventilation
Emrys Kirkman PhD is a Principal Scientist (Physiologist) at Dstl, Porton Down, and is an Honorary Senior Lecturer in Physiology at the University of Durham, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
PHYSIOLOGY
the resulting Hþ in the blood is irrelevant for the central chemoreceptors because Hþ cannot diffuse across the bloodebrain barrier in healthy individuals. Having given the detailed description of the response of the central chemoreceptors to extracellular CSF Hþ, it should be noted that some authors take a different view and argue that the central chemoreceptors respond to a change in intracellular Hþ levels resulting from an alteration in extracellular CSF CO2 levels.
and accumulation of CO2 until PaCO2 has again reached normal levels (Figure 1). It is important to control PaCO2 within such narrow limits because any alteration in PaCO2 will in turn modify pH: hypercapnia causes a respiratory acidosis while hypocapnia causes a respiratory alkalosis. Significant changes in extracellular pH can lead to conformational changes in proteins such as enzymes and hence gross disturbances of body function. The primary mechanism responsible for controlling PaCO2 is a reflex originating from the central chemoreceptors. These chemoreceptors comprise a group of cells in the medulla of the brainstem, near the floor of the fourth cerebral ventricle (Figure 1b). The central chemoreceptors are separate and distinct from the cells generating respiratory rhythm, but the central chemoreceptors do normally provide a tonic respiratory ‘drive’. The predominant view is that the central chemoreceptors respond primarily to hydrogen ions (Hþ) rather than directly to CO2. In this scheme the CO2 in the cerebrospinal fluid (CSF) leads to the generation of Hþ (Figure 1b) and stimulation of the chemoreceptors. Because the CSF contains few buffering proteins a change in CO2 levels here causes greater alterations in Hþ levels than in the blood. Since CO2 can cross the bloodebrain barrier with ease, any change in blood CO2 is fairly quickly reflected by an alteration in CSF CO2, and ultimately a change in chemoreceptor activity. Although the same reaction (resulting in elevation of Hþ levels when CO2 levels rise) takes place in the blood,
Control of oxygen tension in arterial blood Oxygen tension in arterial blood (PaO2) is also controlled by a negative feedback reflex. However, PaO2 is not regulated as sensitively as PaCO2 until there has been a considerable fall in PaO2 from the normal levels of approximately 13.3 kPa to about 8.0 kPa, beyond which there is a powerful increase in ventilation. Increases in PaO2 above 13.3 kPa have little effect on ventilation (Figure 2), presumably because humans have not evolved with a threat of hyperbaric oxygen. One reason why this sort of control is appropriate for oxygen relates to the oxyhaemoglobin dissociation curve. Most of the oxygen in normal blood is bound to haemoglobin; hence, it is the amount and degree of saturation of haemoglobin that dictates the amount of oxygen carried in blood (CaO2). The oxyhaemoglobin dissociation curve is sigmoidal (Figure 2). At normal arterial oxygen tensions haemoglobin is about 98.5% saturated and we are on the upper flat part of the curve. Consequently, falls in PaO2 to about 8.0 kPa have relatively little effect on CaO2. However, falls below this level results in our descent down the steep part of the oxyhaemoglobin curve and consequently large, dangerous, falls in CaO2. Hence, the need for a strong stimulus to breathing is only necessary if PaO2 falls below approximately 8.0 kPa. The receptors responsible for monitoring arterial oxygen tension are the peripheral or arterial chemoreceptors found in the carotid and aortic bodies. These organs receive an enormous blood flow in relation to their mass of tissue. Estimations of the total carotid body blood flow range from 700 to 2000 ml/minute/100 g, which far exceeds the organ’s metabolic demand and hence the venous effluent from the carotid bodies normally have arterial-like oxygen levels. The situation is likely to be similar in the aortic bodies. As a consequence of this high blood flow the tissue derives all of the oxygen needed for metabolic purposes from the plasma rather than needing to extract oxygen from haemoglobin. As a result they effectively monitor the tension of oxygen in plasma (PaO2) rather than the content of oxygen in arterial blood (CaO2). Normally, this arrangement is adequate to monitor blood oxygen levels since the concentration of functional haemoglobin does not usually vary acutely. However, in circumstances where functional haemoglobin levels do drop (e.g. anaemia or carbon monoxide poisoning) CaO2 can drop to dangerously low levels without detection by the arterial chemoreceptors. The arterial chemoreceptors are sensitive to alterations in their blood flow. This is probably the reason why significant haemorrhage quickly leads to increased ventilation as an intense sympathetically-derived vasoconstriction in the arterial chemoreceptors, coupled in severe haemorrhage with reduced arterial blood pressure, causes a marked reduction in chemoreceptor blood flow and hence stagnant hypoxia locally in the chemoreceptors.
a
b
Figure 1a is reproduced from Pocock G, Richards CD. Human Physiology: the basis of medicine. Oxford: Oxford University Press, 2006.
Figure 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
PHYSIOLOGY
chemoreceptors. These individuals are especially troublesome for the anaesthetist because they can stop breathing when some anaesthetic agents (at quite low levels) blunt or abolish the response to hypoxia. In addition, administration of oxygen, by transiently correcting the hypoxia, can also remove the drive to breathe in these individuals.
The effect of acute hypoxia
Impulses/second
8
6
Effects of acidosis and carbon dioxide on arterial chemoreceptors and the whole body response to metabolic acidosis
4
2
0
20
10
0
30
100
The arterial chemoreceptors can also respond to Hþ ions and hence indirectly to CO2 via the Hþ ions it produces (Figure 1b). The effect of Hþ on the arterial chemoreceptors forms the basis of the partial respiratory compensation for a metabolic acidosis. The increase in arterial Hþ concentration (fall in arterial pH) due to the addition of non-volatile acids from metabolic processes leads to the stimulation of arterial chemoreceptors. The resultant increase in respiratory drive elevates ventilation and causes the excretion of more CO2 and hence a lowering of PaCO2. The equation depicted in Figure 1b drifts to the left and Hþ levels fall, restoring arterial pH towards normal. However, the compensation is never complete since the fall in PaCO2 also unloads the central chemoreceptor and hence reduces the respiratory drive from these receptors. The end result is a partial compensation, with some degree of respiratory stimulation from the residual acidosis acting on the arterial chemoreceptors to offset the reduced respiratory drive from the central chemoreceptors because of the lowered PaCO2.
40 kPa 300 mmHg
200 PO2
100
40
Oxyhaemoglobin 80 dissociation curve
30
60
20
40
10
Ventilation
0 16 kPa
0 0 0
4 20
8 40
60 PO2
12 80
20
100
% Saturation of haemoglobin
Ventilation (litres/minute)
50
120 mmHg
Asphyxia: simultaneous elevation in PaCO2 and fall in PaO2
The effect of acute hypoxia on the discharge rate of arterial chemoreceptor afferent nerve fibres (upper graph) and pulmonary ventilation compared with the oxyhaemoglobin dissociation curve (lower graph).
Asphyxia is a very powerful stimulus to increase ventilation. This is because both arterial and central chemoreceptors are activated. The resulting interaction leads to a very marked increase in ventilation (multiplicative effect due to simultaneous activation of the two reflexes; Figure 1a).
Reproduced from Pocock G, Richards CD. Human Physiology: the basis of medicine. Oxford: Oxford University Press, 2006. Figure 2
Longer term hypoxia
Modulation of the arterial chemoreflex by trigeminal and laryngeal reflexes
When hypoxia persists the initial ventilatory stimulation (driven by the arterial chemoreceptors) wanes for 3e5 minutes (a phenomenon called hypoxic ventilatory decline), partly due to the resulting hypocapnia. However, the level of ventilation does persist above the pre-hypoxic level. Continued hypoxia then results in a period of acclimatization whereby CSF Hþ levels are returned to normal by active transport of Hþ across the blood ebrain barrier and the kidneys excreting additional bicarbonate ions (HCO3) to restore blood pH. The detail of these processes is given in the article on the effects of altitude (see volume 8, issue 11) and the end result is a level of ventilation sufficient to prevent hypoxia. It is important to recognize that one group of patients with chronic pulmonary disease, sometimes rather unkindly describes as ‘blue bloaters’, do not make this compensation. (Blue bloaters are so called because they are blue due to the cyanosis of hypoxia and bloated because of congestive heart failure.) ‘Blue bloaters’ adapt to a high PaCO2 and, unlike other individuals, the majority of the drive to breathe in these patients comes from hypoxia acting on the arterial
Stimulation of receptors in the face, nose or pharynx, which relay in the trigeminal nerve, or receptors in the larynx that relay in the superior laryngeal nerve (SLN) cause a reflex apnoea. The reader may be aware of this reflex when standing in the shower and turning on the cold water by mistake; when the cold water hits the head and face it often feels very difficult to breathe. The reflex apnoea resulting from strong stimulation of the trigeminal nerve and SLN is very powerful and can completely block the increase in ventilation initiated by the arterial chemoreceptors (inhibitory interaction). When this occurs the primary cardiovascular response to peripheral chemoreceptor stimulation is unmasked: a powerful vagally mediated bradycardia and an increase in sympathetic tone to the vasculature causing an increase in peripheral resistance. This forms the basis of the diving response. The survival advantage of the diving response is obvious. When an air-breathing animal submerges its head under water it cannot (must not) breathe. It would be disastrous should the activation of the arterial chemoreflex succeed in increasing ventilation under this circumstance, hence the
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
PHYSIOLOGY
advantage of the inhibitory interaction of the respiratory components of the two reflexes (trigeminal and arterial chemoreceptor). The advantage of the bradycardia and selective vasoconstriction is thought to be a reduction in oxygen consumption and a preferential direction of blood flow to the organs most dependent on a constant supply of oxygen. An interaction between arterial chemoreceptor and trigeminal/laryngeal reflexes can arise clinically when the larynx is stimulated. However, it is rare to see the profound bradycardia during intubation of a patient, presumably because patients are very well oxygenated before the procedure is initiated, hence there is no chemoreceptor stimulation. However, marked bradycardia has been reported in tetraplegic patients with high cervical lesions when they are disconnected from a ventilator for routine aspiration of the upper airways. Furthermore, it is possible that this reflex interaction can cause death in extreme cases (e.g. ‘dry drowning’) when a corpse is recovered from the water with no evidence of water inhalation on post mortem examination. Here, it is thought that the bradycardia became so powerful as to cause cardiac arrest.
found as far peripherally as the respiratory bronchioles and alveolar ducts. They relay information to the CNS via myelinated afferent fibres in the vagus. The HeringeBreuer reflex terminates inspiration when the receptors are sufficiently stimulated. They are undoubtedly important in controlling depth of resting ventilation in some animals such as the cat, since loss of the reflex by vagotomy leads to deeper, slower breathing. However, vagotomy does not have this effect in humans and hence the Hering eBreuer reflex probably does not play an important role in setting resting tidal volume in people, but this may become important when breathing at increased tidal volumes.
Other reflexes influencing ventilation A whole host of other reflexes also modify ventilation. These include the pulmonary J receptors found near the pulmonary capillaries and alveoli. These receptors may be responsible for a reflex apnoea seen immediately after exposure of the chest to a blast shock wave associated with an explosion. Under less dramatic circumstances the pulmonary J receptors can lead to rapid shallow breathing and possibly dyspnoea associated with pulmonary oedema. Other protective reflexes such as the irritant receptors (rapidly adapting mechanoreceptors) in the pulmonary airways can give rise to both rapid shallow and deep augmented breaths. The irritant receptors are thought to play a role in reversing the slow progressive collapse of parts of the lungs during prolonged periods of quiet breathing by initiating periodic augmented breaths every 5e20 minutes in resting individuals. Finally, other types of irritant receptors are found in the nose and larynx, which give rise to protective reflexes resulting in coughing and sneezing, respectively. A
Regulating the rate and depth of ventilation Alveolar ventilation (V_ A , approximately 4 litres/minute at rest) is total ventilation rate (V_ T ) minus deadspace ventilation. V_ A ¼ (VT e VD) respiratory rate Equation 1: relation between alveolar ventilation rate (V_ A ), tidal volume (VT), physiological deadspace volume (VD) and respiratory rate. Because deadspace volume is relatively constant in an individual it can be seen from Equation 1 that alveolar ventilation can be achieved by an infinite number of combinations of tidal volumes and respiratory rates, ranging from very slow deep breaths to very rapid shallow breaths. However, the work required to achieve a given alveolar ventilation varies with the combination of tidal volume and respiratory rate chosen, with both extreme examples noted above being associated with increased work of breathing. With deep breathing much work has to be expended against the elastic recoil of the lungs. At the other extreme, very rapid shallow breathing requires much work against airway resistance to gas flow and is wasteful of effort since a greater proportion of each breath represents deadspace ventilation. The precise mechanism whereby an optimal balance is achieved is unclear, but it probably depends on the interaction of a number of sensory factors. One reflex, reported to play a part in balancing rate and depth of ventilation, is the HeringeBreuer reflex. The afferent pathway originates in slowly adapting mechanoreceptors associated with airway smooth muscle of the tracheobronchial tree, which are
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
FURTHER READING Angell-James JE, Daly MB. Some aspects of upper respiratory tract reflexes. Acta Otolaryngol 1975; 79: 242e52. Gray PA, Rekling JC, Bocchiaro CM, Feldman JL. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBotzinger complex. Science 1999; 286: 1566e8. Mathias CJ. Bradycardia and cardiac arrest during tracheal suction e mechanisms in tetraplegic patients. Eur J Intensive Care Med 1976; 2: 147e56. Pandit JJ. Effect of low-dose inhaled anaesthetic agents on the ventilatory response to carbon dioxide in humans: a quantitative review. Anaesthesia 2005; 60: 461e9. Richter DW, Spyer KM. Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends Neurosci 2001; 24: 464e72.
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Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
Respiration: control of ventilation
Learning objectives After reading this article you should be able to describe the: C neural arrangement that produces the basic respiratory rhythm C short-term control of blood carbon dioxide, oxygen, pH and combined changes of these variables C role of the peripheral chemoreceptors in controlling these variables, and of the central chemoreceptors when chronic hypoxia is present (at altitude) C role of neural influences in regulating the chemoreceptor reflexes, as well as in regulating the rate and depth of ventilation
Emrys Kirkman
Abstract Rhythmic ventilation is an automatic process controlled by the central nervous system. Groups of cells in the brainstem, predominantly the ventral and dorsal respiratory groups, are responsible for generating basic respiratory rhythm. This basic rhythm is subject to modulation by both conscious and reflex actions. In normal individuals the respiratory minute volume is set to closely regulate arterial carbon dioxide tension (PaCO2) at approximately 5.3 kPa, predominantly via a negative feedback reflex involving the central chemoreceptors. A separate group of chemoreceptors, the arterial chemoreceptors, are responsible for initiating the increased ventilatory response to counter arterial hypoxia, but a brisk response is not seen until PaO2 levels fall to approximately 8.0 kPa from the normal 13.3 kPa. Combined hypercarbia and hypoxia (asphyxia) is a very powerful stimulus to breathe as the two inputs interact in a synergistic manner. The chemoreceptor reflexes can be modified when the need arises (e.g. blockade of the respiratory part of the arterial chemoreflex by the trigeminal reflex as part of the diving response). Other reflexes such as the HeringeBreuer reflex contribute to setting the balance between tidal volume and respiratory rate to attain a given minute volume, although this reflex does not appear to play a major role in humans at resting tidal volumes. Superimposed on this ‘tonic’ control, additional protective reflexes (e.g. from receptors in the upper airways) are recruited to protect the lungs and airways with responses such as coughs and sneezes when required.
Origin of respiratory rhythm
taken many years and is still continuing. Earlier ideas, based on experiments where gross changes in patterns of breathing were seen following transactions and focal lesions in the brainstem led to the concept of multiple respiratory ‘centres’ (e.g. apneustic and pneumotaxic centres), which interacted to provide respiratory rhythm. This type of concept is now outdated and the altered pattern of breathing seen in these experiments is now viewed as the result of general damage rather than disconnecting specific centres. Control of ventilation is affected by clusters of neurones that are grouped in several distinct areas of the brainstem. Two such areas in the medulla are called the ventral respiratory group (VRG) and the dorsal respiratory group (DRG). Current thinking is that rhythm generation is the domain of a group of tightly clustered neurones in the VRG (specifically in the rostral ventrolateral medulla) called the pre-Botzinger complex (PBC). Although the PBC is itself a complex area containing a heterogeneous population of neurones, the PBC neurones thought to be responsible for respiratory rhythmogenesis are all interneurones in the sense that they have no axons projecting out of the brainstem. PBC neurones then ‘drive’ groups of inspiratory neurones. A strong piece of evidence suggesting that the PBC neurones are indeed the respiratory rhythm generator is the finding that a small focal lesion in this area produces an immediate fatal apnoea. In addition, the VRG is viewed as being more important than the DRG in the generation of respiratory rhythm because the DRG has not been found in a number of species. The inspiratory neurones have a major output into the spinal cord and relevant cranial nuclei to influence the activity of relevant motorneurones. Other areas in the brain that influence the VRG (and DRG) are thought to modify the pattern of breathing, especially depth. One of these areas is the apneustic centre or Botzinger complex (Kolliker-fuse area) of the pons. Experimental evidence suggests that disruption of any of these areas (other than the PBC) will modify the depth or pattern of breathing, but will not abolish rhythmogenesis.
The search for the area(s) of the brain and underlying mechanisms responsible for setting the basic respiratory rhythm has
Control of carbon dioxide tension in arterial blood
Keywords Aortic bodies; arterial chemoreceptors; carotid bodies; central chemoreceptors; diving response; HeringeBreuer reflex; respiratory rhythm Royal College of Anaesthetists CPD Matrix: 1A01
Ventilation is an automatic process that is controlled by the central nervous system. The brainstem is a key area responsible for the basic respiratory rhythm. This in turn is modulated by a number of influences ranging from conscious alterations (originating form ‘higher centres’), tonic reflexes such as the chemoreceptor reflexes regulating carbon dioxide levels of the blood and preventing dangerous hypoxia to episodic reflexes such as coughing and sneezing.
Carbon dioxide tension in arterial blood (PaCO2) is very closely regulated around a set point (5.3 kPa or 40 mmHg in a healthy individual) by a negative feedback system. A rise in PaCO2 stimulates a reflex increase in ventilation, excreting excess CO2 and returning PaCO2 to the set point. Conversely, a fall in CO2 attenuates tonic respiratory drive, resulting in a fall in ventilation
Emrys Kirkman PhD is a Principal Scientist (Physiologist) at Dstl, Porton Down, and is an Honorary Senior Lecturer in Physiology at the University of Durham, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
PHYSIOLOGY
the resulting Hþ in the blood is irrelevant for the central chemoreceptors because Hþ cannot diffuse across the bloodebrain barrier in healthy individuals. Having given the detailed description of the response of the central chemoreceptors to extracellular CSF Hþ, it should be noted that some authors take a different view and argue that the central chemoreceptors respond to a change in intracellular Hþ levels resulting from an alteration in extracellular CSF CO2 levels.
and accumulation of CO2 until PaCO2 has again reached normal levels (Figure 1). It is important to control PaCO2 within such narrow limits because any alteration in PaCO2 will in turn modify pH: hypercapnia causes a respiratory acidosis while hypocapnia causes a respiratory alkalosis. Significant changes in extracellular pH can lead to conformational changes in proteins such as enzymes and hence gross disturbances of body function. The primary mechanism responsible for controlling PaCO2 is a reflex originating from the central chemoreceptors. These chemoreceptors comprise a group of cells in the medulla of the brainstem, near the floor of the fourth cerebral ventricle (Figure 1b). The central chemoreceptors are separate and distinct from the cells generating respiratory rhythm, but the central chemoreceptors do normally provide a tonic respiratory ‘drive’. The predominant view is that the central chemoreceptors respond primarily to hydrogen ions (Hþ) rather than directly to CO2. In this scheme the CO2 in the cerebrospinal fluid (CSF) leads to the generation of Hþ (Figure 1b) and stimulation of the chemoreceptors. Because the CSF contains few buffering proteins a change in CO2 levels here causes greater alterations in Hþ levels than in the blood. Since CO2 can cross the bloodebrain barrier with ease, any change in blood CO2 is fairly quickly reflected by an alteration in CSF CO2, and ultimately a change in chemoreceptor activity. Although the same reaction (resulting in elevation of Hþ levels when CO2 levels rise) takes place in the blood,
Control of oxygen tension in arterial blood Oxygen tension in arterial blood (PaO2) is also controlled by a negative feedback reflex. However, PaO2 is not regulated as sensitively as PaCO2 until there has been a considerable fall in PaO2 from the normal levels of approximately 13.3 kPa to about 8.0 kPa, beyond which there is a powerful increase in ventilation. Increases in PaO2 above 13.3 kPa have little effect on ventilation (Figure 2), presumably because humans have not evolved with a threat of hyperbaric oxygen. One reason why this sort of control is appropriate for oxygen relates to the oxyhaemoglobin dissociation curve. Most of the oxygen in normal blood is bound to haemoglobin; hence, it is the amount and degree of saturation of haemoglobin that dictates the amount of oxygen carried in blood (CaO2). The oxyhaemoglobin dissociation curve is sigmoidal (Figure 2). At normal arterial oxygen tensions haemoglobin is about 98.5% saturated and we are on the upper flat part of the curve. Consequently, falls in PaO2 to about 8.0 kPa have relatively little effect on CaO2. However, falls below this level results in our descent down the steep part of the oxyhaemoglobin curve and consequently large, dangerous, falls in CaO2. Hence, the need for a strong stimulus to breathing is only necessary if PaO2 falls below approximately 8.0 kPa. The receptors responsible for monitoring arterial oxygen tension are the peripheral or arterial chemoreceptors found in the carotid and aortic bodies. These organs receive an enormous blood flow in relation to their mass of tissue. Estimations of the total carotid body blood flow range from 700 to 2000 ml/minute/100 g, which far exceeds the organ’s metabolic demand and hence the venous effluent from the carotid bodies normally have arterial-like oxygen levels. The situation is likely to be similar in the aortic bodies. As a consequence of this high blood flow the tissue derives all of the oxygen needed for metabolic purposes from the plasma rather than needing to extract oxygen from haemoglobin. As a result they effectively monitor the tension of oxygen in plasma (PaO2) rather than the content of oxygen in arterial blood (CaO2). Normally, this arrangement is adequate to monitor blood oxygen levels since the concentration of functional haemoglobin does not usually vary acutely. However, in circumstances where functional haemoglobin levels do drop (e.g. anaemia or carbon monoxide poisoning) CaO2 can drop to dangerously low levels without detection by the arterial chemoreceptors. The arterial chemoreceptors are sensitive to alterations in their blood flow. This is probably the reason why significant haemorrhage quickly leads to increased ventilation as an intense sympathetically-derived vasoconstriction in the arterial chemoreceptors, coupled in severe haemorrhage with reduced arterial blood pressure, causes a marked reduction in chemoreceptor blood flow and hence stagnant hypoxia locally in the chemoreceptors.
a
b
Figure 1a is reproduced from Pocock G, Richards CD. Human Physiology: the basis of medicine. Oxford: Oxford University Press, 2006.
Figure 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
PHYSIOLOGY
chemoreceptors. These individuals are especially troublesome for the anaesthetist because they can stop breathing when some anaesthetic agents (at quite low levels) blunt or abolish the response to hypoxia. In addition, administration of oxygen, by transiently correcting the hypoxia, can also remove the drive to breathe in these individuals.
The effect of acute hypoxia
Impulses/second
8
6
Effects of acidosis and carbon dioxide on arterial chemoreceptors and the whole body response to metabolic acidosis
4
2
0
20
10
0
30
100
The arterial chemoreceptors can also respond to Hþ ions and hence indirectly to CO2 via the Hþ ions it produces (Figure 1b). The effect of Hþ on the arterial chemoreceptors forms the basis of the partial respiratory compensation for a metabolic acidosis. The increase in arterial Hþ concentration (fall in arterial pH) due to the addition of non-volatile acids from metabolic processes leads to the stimulation of arterial chemoreceptors. The resultant increase in respiratory drive elevates ventilation and causes the excretion of more CO2 and hence a lowering of PaCO2. The equation depicted in Figure 1b drifts to the left and Hþ levels fall, restoring arterial pH towards normal. However, the compensation is never complete since the fall in PaCO2 also unloads the central chemoreceptor and hence reduces the respiratory drive from these receptors. The end result is a partial compensation, with some degree of respiratory stimulation from the residual acidosis acting on the arterial chemoreceptors to offset the reduced respiratory drive from the central chemoreceptors because of the lowered PaCO2.
40 kPa 300 mmHg
200 PO2
100
40
Oxyhaemoglobin 80 dissociation curve
30
60
20
40
10
Ventilation
0 16 kPa
0 0 0
4 20
8 40
60 PO2
12 80
20
100
% Saturation of haemoglobin
Ventilation (litres/minute)
50
120 mmHg
Asphyxia: simultaneous elevation in PaCO2 and fall in PaO2
The effect of acute hypoxia on the discharge rate of arterial chemoreceptor afferent nerve fibres (upper graph) and pulmonary ventilation compared with the oxyhaemoglobin dissociation curve (lower graph).
Asphyxia is a very powerful stimulus to increase ventilation. This is because both arterial and central chemoreceptors are activated. The resulting interaction leads to a very marked increase in ventilation (multiplicative effect due to simultaneous activation of the two reflexes; Figure 1a).
Reproduced from Pocock G, Richards CD. Human Physiology: the basis of medicine. Oxford: Oxford University Press, 2006. Figure 2
Longer term hypoxia
Modulation of the arterial chemoreflex by trigeminal and laryngeal reflexes
When hypoxia persists the initial ventilatory stimulation (driven by the arterial chemoreceptors) wanes for 3e5 minutes (a phenomenon called hypoxic ventilatory decline), partly due to the resulting hypocapnia. However, the level of ventilation does persist above the pre-hypoxic level. Continued hypoxia then results in a period of acclimatization whereby CSF Hþ levels are returned to normal by active transport of Hþ across the blood ebrain barrier and the kidneys excreting additional bicarbonate ions (HCO3) to restore blood pH. The detail of these processes is given in the article on the effects of altitude (see volume 8, issue 11) and the end result is a level of ventilation sufficient to prevent hypoxia. It is important to recognize that one group of patients with chronic pulmonary disease, sometimes rather unkindly describes as ‘blue bloaters’, do not make this compensation. (Blue bloaters are so called because they are blue due to the cyanosis of hypoxia and bloated because of congestive heart failure.) ‘Blue bloaters’ adapt to a high PaCO2 and, unlike other individuals, the majority of the drive to breathe in these patients comes from hypoxia acting on the arterial
Stimulation of receptors in the face, nose or pharynx, which relay in the trigeminal nerve, or receptors in the larynx that relay in the superior laryngeal nerve (SLN) cause a reflex apnoea. The reader may be aware of this reflex when standing in the shower and turning on the cold water by mistake; when the cold water hits the head and face it often feels very difficult to breathe. The reflex apnoea resulting from strong stimulation of the trigeminal nerve and SLN is very powerful and can completely block the increase in ventilation initiated by the arterial chemoreceptors (inhibitory interaction). When this occurs the primary cardiovascular response to peripheral chemoreceptor stimulation is unmasked: a powerful vagally mediated bradycardia and an increase in sympathetic tone to the vasculature causing an increase in peripheral resistance. This forms the basis of the diving response. The survival advantage of the diving response is obvious. When an air-breathing animal submerges its head under water it cannot (must not) breathe. It would be disastrous should the activation of the arterial chemoreflex succeed in increasing ventilation under this circumstance, hence the
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Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006
PHYSIOLOGY
advantage of the inhibitory interaction of the respiratory components of the two reflexes (trigeminal and arterial chemoreceptor). The advantage of the bradycardia and selective vasoconstriction is thought to be a reduction in oxygen consumption and a preferential direction of blood flow to the organs most dependent on a constant supply of oxygen. An interaction between arterial chemoreceptor and trigeminal/laryngeal reflexes can arise clinically when the larynx is stimulated. However, it is rare to see the profound bradycardia during intubation of a patient, presumably because patients are very well oxygenated before the procedure is initiated, hence there is no chemoreceptor stimulation. However, marked bradycardia has been reported in tetraplegic patients with high cervical lesions when they are disconnected from a ventilator for routine aspiration of the upper airways. Furthermore, it is possible that this reflex interaction can cause death in extreme cases (e.g. ‘dry drowning’) when a corpse is recovered from the water with no evidence of water inhalation on post mortem examination. Here, it is thought that the bradycardia became so powerful as to cause cardiac arrest.
found as far peripherally as the respiratory bronchioles and alveolar ducts. They relay information to the CNS via myelinated afferent fibres in the vagus. The HeringeBreuer reflex terminates inspiration when the receptors are sufficiently stimulated. They are undoubtedly important in controlling depth of resting ventilation in some animals such as the cat, since loss of the reflex by vagotomy leads to deeper, slower breathing. However, vagotomy does not have this effect in humans and hence the Hering eBreuer reflex probably does not play an important role in setting resting tidal volume in people, but this may become important when breathing at increased tidal volumes.
Other reflexes influencing ventilation A whole host of other reflexes also modify ventilation. These include the pulmonary J receptors found near the pulmonary capillaries and alveoli. These receptors may be responsible for a reflex apnoea seen immediately after exposure of the chest to a blast shock wave associated with an explosion. Under less dramatic circumstances the pulmonary J receptors can lead to rapid shallow breathing and possibly dyspnoea associated with pulmonary oedema. Other protective reflexes such as the irritant receptors (rapidly adapting mechanoreceptors) in the pulmonary airways can give rise to both rapid shallow and deep augmented breaths. The irritant receptors are thought to play a role in reversing the slow progressive collapse of parts of the lungs during prolonged periods of quiet breathing by initiating periodic augmented breaths every 5e20 minutes in resting individuals. Finally, other types of irritant receptors are found in the nose and larynx, which give rise to protective reflexes resulting in coughing and sneezing, respectively. A
Regulating the rate and depth of ventilation Alveolar ventilation (V_ A , approximately 4 litres/minute at rest) is total ventilation rate (V_ T ) minus deadspace ventilation. V_ A ¼ (VT e VD) respiratory rate Equation 1: relation between alveolar ventilation rate (V_ A ), tidal volume (VT), physiological deadspace volume (VD) and respiratory rate. Because deadspace volume is relatively constant in an individual it can be seen from Equation 1 that alveolar ventilation can be achieved by an infinite number of combinations of tidal volumes and respiratory rates, ranging from very slow deep breaths to very rapid shallow breaths. However, the work required to achieve a given alveolar ventilation varies with the combination of tidal volume and respiratory rate chosen, with both extreme examples noted above being associated with increased work of breathing. With deep breathing much work has to be expended against the elastic recoil of the lungs. At the other extreme, very rapid shallow breathing requires much work against airway resistance to gas flow and is wasteful of effort since a greater proportion of each breath represents deadspace ventilation. The precise mechanism whereby an optimal balance is achieved is unclear, but it probably depends on the interaction of a number of sensory factors. One reflex, reported to play a part in balancing rate and depth of ventilation, is the HeringeBreuer reflex. The afferent pathway originates in slowly adapting mechanoreceptors associated with airway smooth muscle of the tracheobronchial tree, which are
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FURTHER READING Angell-James JE, Daly MB. Some aspects of upper respiratory tract reflexes. Acta Otolaryngol 1975; 79: 242e52. Gray PA, Rekling JC, Bocchiaro CM, Feldman JL. Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBotzinger complex. Science 1999; 286: 1566e8. Mathias CJ. Bradycardia and cardiac arrest during tracheal suction e mechanisms in tetraplegic patients. Eur J Intensive Care Med 1976; 2: 147e56. Pandit JJ. Effect of low-dose inhaled anaesthetic agents on the ventilatory response to carbon dioxide in humans: a quantitative review. Anaesthesia 2005; 60: 461e9. Richter DW, Spyer KM. Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends Neurosci 2001; 24: 464e72.
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Kirkman E, Respiration: control of ventilation, Anaesthesia and intensive care medicine (2017), https://doi.org/ 10.1016/j.mpaic.2017.09.006