Which of the following is the primary stimulus to breathe in normal human beings?

Control of Breathing and Physiologic Contributions to Immature Respiratory Control

Respiratory control and its maturation is under tight regulation, with interplay from the central and peripheral nervous systems and feedback from the lung parenchyma and airway musculature. Our still limited knowledge of the normal and pathophysiologic developmental pathways governing the control of breathing comes from both human and animal studies. Understanding the normal developmental trajectory and maturation of each component coupled with its modification by postnatal environmental factors can inform clinicians about the magnitude of disordered breathing control in preterm and former preterm infants, providing guidelines for monitoring and targets for treatment.

Chapter 4 Control of breathing

•

Rhythmic breathing patterns commence in utero and continue, uninterrupted, for many decades. The origin of this rhythm is a group of interconnected neurones in the medulla of the brainstem, known as the central pattern generator (CPG). Approximately six groups of neurones exist, each of which is activated at different times, and controlled by a series of positive and negative feedback systems on each other. Unlike the heart there is no single pacemaker cell, providing physiological ‘redundancy’ such that many cells in each group can be damaged or inhibited without affecting the breathing rhythm. Many neurotransmitters are involved in the CPG, with glutamate being the predominant excitatory molecule and glycine the major inhibitor.

The various groups of neurones in the CPG have direct effects on the lower motor neurones to different groups of respiratory muscles, such as those of the airway, chest wall and diaphragm during inspiration, and the abdominal and other expiratory muscles when active expiration is required.

Many other central nervous system connections influence the CPG activity. The pons acts as a coordinator of the various inputs into the brainstem that affect respiration, exerting fine control over the CPG. The most important influence on the CPG is the cerebral cortex, which can control respiration either consciously, for example, during breath holding, or unconsciously, for example, during speech, singing, coughing, etc. or even when the chemical drive to breathe is removed when cortical input prevents apnoea.

Peripheral nervous system connections to the respiratory centre give rise to numerous reflexes. Irritant receptors in the airway wall from the nose down to deep in the lung give rise to protective reflexes causing sneezing, coughing and secretion of airway lining fluid to help remove large inhaled particles. Inhaled chemicals, for example, tobacco smoke, have similar effects and may also lead to laryngospasm and bronchospasm. Stimulation also causes cardiovascular changes, particularly hypertension and tachycardia. Mechanoreceptors in the pharynx sense pressure and feedback to the brainstem to increase activity in pharyngeal dilator muscles.

The cough reflex involves three phases: inspiration; compression, when the expiratory muscles contract against a closed glottis; and expulsion, when the glottis opens and air is expelled at high velocity. The turbulent and high flow of gas pulls mucous from the airway wall and expels it from the respiratory tract into the pharynx.

The lungs contain stretch receptors, which are broadly divided into slowly adapting or rapidly adapting groups, the former acting as lung volume sensors and the latter as sensors of lung volume change or as nociceptors. Many reflexes arise from these receptors, the most well known is the Hering–Breuer reflex in which lung inflation increases the rate of firing of stretch receptors which inhibits inspiration. This, and other lung volume-based reflexes, are of little importance in the normal control of breathing in adults, but may be important in neonates. Conversely, afferent nerves from muscle spindles in the diaphragm are important in controlling muscle contraction during breathing, and involved in the perception of increased inspiratory loading

Carbon dioxide has a major influence on breathing, with a linear relationship between Pco2 and minute ventilation (tidal volume × respiratory rate). The Pco2 ventilation line is variable between individuals, and within an individual is affected by many factors such as pH, hypoxia, diurnal variation and various hormones.

The reflex response to carbon dioxide occurs predominantly in the central chemoreceptors, located close to the surface of the ventral medulla. Carbon dioxide in the blood diffuses freely across the blood–brain barrier and hydrates into carbonic acid causing a fall in pH. Change in pH is detected by the medulla by an unknown mechanism, possibly involving potassium channels. If the Pco2 remains elevated for several hours, a compensatory change in cerebrospinal fluid bicarbonate occurs which partially corrects the pH and restores ventilation back towards normal.

Hypoxia also has a profound effect on the control of ventilation. This is a funda­mental protective reflex present in most mammals. In response to progressive hypoxia ventilation increases in a hyperbolic fashion, beginning to increase at an arterial Po2 of approximately 10 kPa (75 mmHg) and with significant hyperventilation occurring at values below 8 kPa (60 mmHg). In the same way that the ventilatory response to carbon dioxide is affected by hypoxia, the hypoxic ventilatory response is influenced by carbon dioxide and pH, such that in the presence of both hypoxia and hypercapnia minute ventilation is normally very high.

The acute ventilatory response to hypoxia is mediated mostly at the peripheral chemoreceptors, which are located in the carotid bodies at the bifurcation of each common carotid artery. Oxygen sensing occurs in the glomus cells of the carotid body, and involves inhibition of a potassium channel either as a direct result of hypoxia on the channel, but more probably mediated by changing levels of reactive oxygen species, nitric oxide or hydrogen sulphide. Acetylcholine and adenosine triphosphate are the neurotransmitters involved in the carotid body, with a range of other molecules acting as modulators of the response including dopamine.

With hypoxia lasting longer than a few minutes the response reduces, a change referred to as hypoxic ventilatory decline, which is believed to be mediated centrally rather than in the carotid bodies. If hypoxic conditions are sustained for several hours ventilation increases gradually for about 24 h and remains elevated for several days until acclimatisation occurs, as seen at high altitude.

Voluntary breath holding represents a dramatic example of the cerebral cortex overriding the CPG, and results in a progressive fall in arterial Po2 and a rise in Pco2. After a variable length of time, at the ‘breaking point,’ the subject exhales and breathes again. The levels of arterial blood gases at the breaking point are consistent, with the Po2 probably more important, as breathing oxygen before breath holding prolongs the time taken to reach the breaking point. Afferent input from the respiratory muscles and chest wall also contributes to the urge to breathe during a breath hold, and causes involuntary respiratory movements to occur just before the breaking point.

Several drugs affect respiratory control, with all sedatives and anaesthetics, including alcohol, depressing both resting ventilation and the ventilatory responses to carbon dioxide or hypoxia. For example, all opioids cause a profound dose-dependent effect, initially slowing the respiratory rate but also reducing tidal volume in many situations, with fast-acting opioids, as used during general anaesthesia, routinely causing apnoea. Neonates are more susceptible to the effects of opioids, and the same may also be true for children, particularly those with obstructive sleep apnoea. Respiratory stimulants such as doxapram act on the peripheral chemoreceptors to increase ventilation, but their effects are nonspecific, so the use is limited by central nervous system stimulation causing side effects.

Assessment of the ventilatory response to stimulation is difficult and rarely done due to the hazards of rendering subjects either hypoxic or hypercapnic. In both situations, techniques are described for measuring ventilation while rebreathing gas mixtures to cause progressive changes in carbon dioxide or hypoxia levels or by using steady-state changes in gas concentrations.

Control of breathing

Control of breathing is under both voluntary (“behavioral”) and involuntary (“metabolic”) control and requires input to the central chemoreceptors of the brainstem (pons/medulla) from the cortex, peripheral chemoreceptors, and respiratory muscles. The limbic system and hypothalamus also have input that may be associated with emotions. There is a degree of voluntary control from the cortex that more easily leads to hyperventilation than hypoventilation (West, 2012). When awake, breathing is modulated by both processes. Metabolic control of breathing is solely present during NREM sleep leading to a stable, regular pattern in the normal state. Breathing during REM sleep is irregular and likely impacted by a degree of behavioral control that may occur during dreaming (Kryger, 2005). Due to decreased muscle tone in REM sleep which impacts both the upper airway and respiratory muscles, hypoventilation and obstructive sleep apnea can be found predominately or solely in the REM sleep state. This contrasts with the rare disorders of central hypoventilation that impact breathing and ventilation in NREM sleep and even wakefulness. The hypothalamus is noted to augment breathing during exercise and can impact the hypoxemic and ventilatory responses (Katz et al., 2000). PHOX2B mutations are the disease-causing mutation in CCHS and these genes are expressed in areas responsible for metabolic control of breathing as well as the autonomic nervous system.

In children chronic hypoventilation is rare in the absence of a defect in the pulmonary, cardiac, brain, or neuromuscular disease and requires further evaluation. The sleep related hypoventilation see in ROHHAD is thought to be secondary to the impaired autonomic control of ventilation while the voluntary control of ventilation is intact or relatively intact (less impairment). Individuals with ROHHAD have an abnormal response to carbon dioxide challenge whether this is endogenous or exogenous and is thought to vary in severity between individuals with this disorder (Carroll et al., 2010). A small cohort of children with ROHHAD has been tested extensively in their hypoxemic and hyperventilatory responses to laboratory challenges (Carroll et al., 2010) and were found to have more subtle awake deficits in control of breathing although behaviorally had little response to these challenges. It was proposed that perhaps the difficulties they experience with control of breathing are compounded by the obesity which impacts respiratory muscle function and control of breathing in adults with OHS.

In both the disorders of ROHHAD and CCHS, control of breathing and autonomic dysfunction are impacted and it has been suggested that this may represent a rare grouping of disorders (Rand et al., 2013).

Breathing Is Automatic and Not Autonomic

The control of breathing is an automatic process that works without conscious intervention when asleep, anesthetized, or awake and not specifically thinking about breathing. Conscious factors can override or modify automatic functions of the respiratory control system for a limited period. For example, an individual can voluntarily speak, smell, hyperventilate, or hold their breath. However, automatic functions ultimately mandate a return to normal breathing. Because the control of breathing is largely automatic and the regulation of breathing is intimately associated with autonomic functions, the respiratory control system is often confused as part of the autonomic nervous system. However, ventilatory control is in many respects more similar to systems controlling somatic motor functions, such as walking.

Asphyxia

It is very rare for either arterial Po2, Pco2 or H+ of a healthy individual to change without changes in the other two (unless you fall into the hands of a respiratory physiologist). The stimulus to breathe that builds up when you hold your breath or rebreathe from a plastic bag involves changes in all three of these variables.

The overall effect of changes in all three was described by a formula devised by Gray in 1945:

VR=0.22[H+]+0.26Pco2-18+105/100.038 Po2

where VR is the ratio of ventilation during asphyxia to unstimulated ventilation. This formula is more important as an illustration that no single factor controls ventilation than as a quantitative estimate.

The way in which hypoxia and hypercapnia combine to stimulate breathing is shown in Figure 9.7, where each curve represents a Pco2/V˙E relationship at a different Po2. With progressive hypoxia the curves are seen to steepen, producing a greater ventilatory response than would be produced by the simple sum of the two stimuli. On the other hand, it is not unusual for the arterial Po2, Pco2 or [H+] of patients to be changed independently by their disease. Most usually this change consists of a fall in Po2 while Pco2 is maintained close to normal.

Chemical control of breathing determines minute ventilation, with changes taking place over a matter of one or more minutes. The pattern of breathing that makes up this minute ventilation is determined by the neural control of ventilation, which can bring about changes in pattern in fractions of a second. This process is dealt with in Chapter 10.

Summary 2

Increased levels of arterial Pco2 (hypercapnia) stimulate both central and peripheral chemoreceptors.

Unlike oxygen lack, the smallest increase in Pco2 stimulates breathing.

CO2 forms hydrogen ions which are the specific stimulus to the receptors.

Asphyxia is a combination of hypoxia and hypercapnia and the ventilatory response to it is greater than the response to the sum of its parts.

Response to chronic hypercapnia reduces with time because the environment of the central chemoreceptors is actively restored to normal.

Disorders of Voluntary Breathing

Voluntary control of breathing is mediated primarily via the corticospinal and corticobulbar tracts and is important in activities such as speech, singing, and voluntary breath holding. Disorders involving this mechanism occur mainly in bilateral pontine infarctions and lesions involving the pontine tegmentum that interrupt the descending motor pathways. The classical situation is that of patients with a “locked-in” syndrome. Such patients have a constant unvarying respiratory rhythm that cannot be modulated voluntarily. Thus, they are unable to hold their breath, breathe in deeply, or cough voluntarily. Reflex responses and responses to chemoreceptors remain intact. Partial lesions of the high cervical cord that selectively involve the corticospinal tracts at the C3-C4 segments can also produce a similar condition.7

An analogous disorder occurs in patients with bilateral hemispherical disorders (especially elderly patients with diffuse cerebrovascular disease). Such patients can have a respiratory “apraxia” in which they are unable to voluntarily hold their breath or take a deep breath on command. Swallowing on command is also impaired, although automatic swallowing is preserved. These patients commonly also display other “release reflexes” such as frontal release reflexes and gegenhalten.

Introduction

The neural control of breathing and its role in human disease has been the subject of intensive research. Much of this effort has been aimed at identifying neurons that act as central respiratory chemoreceptors (CRCs) – neurons that sense changes in CO2 and initiate ventilatory changes that help maintain pH homeostasis. In this chapter, we discuss evidence that 5-HT neurons are CRCs. We review their role in the control of breathing and the ventilatory response to hypercapnia, and discuss data showing they have intrinsic chemosensitivity. We also review data from mice in which 5-HT neurons are genetically deleted, and in which there is a large decrease in the response to increased CO2. Finally, we discuss the implications for human disease.

Voluntary Control of Breathing

Voluntary control of breathing is mediated by the descending corticospinal tract and its influence on the motor neurons innervating the diaphragm and intercostal muscles. The rate and rhythm of breathing are influenced by the forebrain, as observed during voluntary hyperventilation or breath-holding, as well as during the semivoluntary or involuntary rhythmic alterations in ventilatory pattern that are required during speech, singing, laughing, and crying.

Electrophysiologic and imaging studies have shown that specific areas of cortex are involved in different phases of voluntary breathing. The diaphragm can be activated by stimulation of the contralateral motor cortex using transcranial magnetic stimulation. The diaphragm lacks significant bilateral cortical representation, consistent with the finding of attenuation of diaphragmatic excursion only on the hemiplegic side in patients with hemispheric stroke, and intercostal muscles are similarly affected by hemispheric lesions. Positron emission tomographic studies have shown an increase in cerebral blood flow in the primary motor cortex bilaterally, the right supplementary motor cortex, and the ventrolateral thalamus during inspiration; and the same structures, along with the cerebellum, are involved in expiration.

The involvement of the forebrain in the regulation of breathing is further substantiated by the induction of apnea that follows stimulation of the anterior portion of the hippocampal gyrus, the ventral and medial surfaces of the temporal lobe, and the anterior portion of the insula.

Brain Stem/Central Control of Breathing

Central control of breathing is complex and incompletely understood. Anatomically, key groups of neurons located in the upper pons include the pontine respiratory group (containing the nucleus parabrachialis medialis and lateralis and the Kolliker–Fuse nucleus). This area was previously referred to as the pneumotaxic center as it is thought to be involved in the inspiratory off-switch. The lower pontine reticular formation (sometimes referred to as the apneustic center because ablative lesions above this site cause prolonged inspiratory gasps) is believed to elicit a tonic excitation to inspiratory premotor neurons.

In the medulla, the dorsal respiratory group, which is associated with the nucleus tractus solitarius processes afferent information from phrenic, vagus, and peripheral chemoreceptors to the higher centers. This group of neurons contains many inspiration-related neurons, some of which are believed to be involved in an ‘inspiratory off-switch.’ It is uncertain if there is direct phrenic output but there are projections to the retrotrapezoid nucleus and to the nearby ventral respiratory group. The ventral respiratory group contains the pre-Botzinger complex, believed to comprise key pacemaker neurons on the basis of the presence of a respiratory rhythm in minimal slice preparations. Conversely, the Botzinger complex is believed to have expiratory active/inspiratory inhibitory neurons. The rostral ventral respiratory group contains inspiratory premotor neurons and a group of neurons known as the nucleus ambiguous, which provides motor output to the larynx and pharynx via the vagi.

Neurochemical control of breathing

The control of breathing involves interaction of both chemical and neural receptors found in the peripheral and central nervous system as well as end organs. The neural receptors are found in upper airway, respiratory muscles, lungs, and pulmonary vessels (Bolton et al., 2004). These include muscle spindles, and pulmonary stretch receptors responding to changes in lung volumes and thoracic cavity pressure. There have been multiple different types of pulmonary sensory receptors identified including fast and slow adapting (stretch) receptors and C-fiber receptors (J receptors) (Widdicombe, 1982, 2001; Brouns et al., 2012). These receptors detect changes in lung tidal volumes. Slow adapting fibers seem to have a role in inflation reflex and terminate inspiration and prolong expiration (Schelegle, 2003). Fast adapting fibers regulate deflation reflex and mediate deep augmented breaths. C-fiber receptor (J receptors, previously known as juxtapulmonary receptors) stimulation causes reflex increase in breathing rate and is also important in the detection of dyspnea. This J receptor-mediated reflex initially causes apnea followed by rapid, shallow breathing, bradycardia, and hypotension mediated by the vagal nerve. In addition, J receptors also play a role in bronchoconstriction, laryngospasm, airway mucus secretion, and bronchial and nasal vasodilatation (Paintal, 1995; Sant’Ambrogio and Widdicombe, 2001; Widdicombe, 2001).

The peripheral chemoreceptors include the carotid and aortic bodies and are primarily sites that respond to changes in PaO2 but they also modulate their activity to PaCO2 and pH changes (Honda and Tani, 1999). Neural firings of these receptors are increased in response to PaO2 decrement and increase in PaCO2 concentration with subsequent decrease in pH. There is evidence to suggest that aortic bodies respond more in infancy whereas carotid bodies respond more in adulthood (Daly and Ungar, 1966; Lahiri et al., 1981; Horn and Waldrop 1994). Impulses through these are carried to the central nervous system respiratory modulators as described in sections of neuroanatomy via cranial nerves IX and X. Carotid bodies and their role in hypoxia-induced hyperventilation have been extensively studied (Gonzalez et al., 1995; Milsom and Burleson, 2007). They are composed of glomus cells (also known as type I) and sustentacular cells (type II). Carotid bodies release multiple neurotransmitters under hypoxic stimulation. Glomus cells are believed to be involved in afferent transduction. In animals, it has been shown experimentally that potassium-related channels contribute to neurotransmitter release and act as oxygen sensors (Prabhakar, 2006). Sustentacular cells act as glial cells. Hypoxic stimulus is then transferred to the brainstem through the vagal nerve. Aortic bodies are less well studied but there is experimental evidence that they respond to changes in oxygen saturation whereas carotid bodies seem to respond to changes in PO2 (Lahiri et al., 1981). These peripheral receptors also mediate exercise-related ventilator drive and altitude acclimatization (Dempsey and Smith, 1994; Prabhakar et al., 2009).

Receptors situated in the central nervous system are more important and crucial in maintaining body pH and acid–base balance. They are mostly responsive to CO2 and pH changes. These receptors are present in different areas including the following: the locus ceruleus, the NTS, the midline raphe and ventrolateral quadrant of the medulla (Bianchi et al., 1995; Honda and Tani, 1999; Nattie, 1999; Kara et al., 2003). Increases in CO2 or decreases in pH have been associated with increases in ventilator response by multiple mechanisms even though they are still incompletely understood. These may include increases in conductance of potassium as well as synaptic transmission via several neurotransmitters such as acetylcholine, and glutamate (Nattie, 1999). There is increasing evidence that central respiratory control of breathing is more widespread and may involve suprapontine structures in the hypothalamus, amygdala, and cerebral cortex. Recent fMRI studies have shown that arcuate nucleus firing increases in response to hypercapnia in cats (Honda and Tani, 1999). In addition, it has also been shown that infants who die of sudden infant death syndrome may have depletion of muscarinic receptors in the arcuate nucleus (Kinney, 2009). Studies using PET and fMRI have shown activation of premotor, primary motor, and supplementary motor cortex areas during increased respiratory drive (Horn and Waldrop, 1994). Future studies using physiologic approaches such as PET and fMRI are expected to shed further light on nervous control of breathing.