Respiratory Drive

Introduction

This article is taken from portions of the Britannica Human Respiration System article and readers should consult the complete article at this address. Britannica Human Respiratory System This portion of the article is reproduced here in order to assist members with a basic understanding of respiratory drive mechanisms that influence our understanding of obstructive and central apnea, and the mechanisms that stimulate us to breathe.

Control of breathing

Breathing is an automatic and rhythmic act produced by networks of neurons in the hindbrain (the pons and medulla). The neural networks direct muscles that form the walls of the thorax and abdomen and produce pressure gradients that move air into and out of the lungs. The respiratory rhythm and the length of each phase of respiration are set by reciprocal stimulatory and inhibitory interconnection of these brain-stem neurons.

An important characteristic of the human respiratory system is its ability to adjust breathing patterns to changes in both the internal milieu and the external environment. Ventilation increases and decreases in proportion to swings in carbon dioxide production and oxygen consumption caused by changes in metabolic rate. The respiratory system is also able to compensate for disturbances that affect the mechanics of breathing, such as the airway narrowing that occurs in an asthmatic attack. Breathing also undergoes appropriate adjustments when the mechanical advantage of the respiratory muscles is altered by postural changes or by movement.

This flexibility in breathing patterns in large part arises from sensors distributed throughout the body that send signals to the respiratory neuronal networks in the brain. Chemoreceptors detect changes in blood oxygen levels and change the acidity of the blood and brain. Mechanoreceptors monitor the expansion of the lung, the size of the airway, the force of respiratory muscle contraction, and the extent of muscle shortening.

Although the diaphragm is the major muscle of breathing, its respiratory action is assisted and augmented by a complex assembly of other muscle groups. Intercostal muscles inserting on the ribs, the abdominal muscles, and muscles such as the scalene and sternocleidomastoid that attach both to the ribs and to the cervical spine at the base of the skull also play an important role in the exchange of air between the atmosphere and the lungs. In addition, laryngeal muscles and muscles in the oral and nasal pharynx adjust the resistance of movement of gases through the upper airways during both inspiration and expiration. Although the use of these different muscle groups adds considerably to the flexibility of the breathing act, they also complicate the regulation of breathing. These same muscles are used to perform a number of other functions, such as speaking, chewing and swallowing, and maintaining posture. Perhaps because the “respiratory” muscles are employed in performing nonrespiratory functions, breathing can be influenced by higher brain centres and even controlled voluntarily to a substantial degree. An outstanding example of voluntary control is the ability to suspend breathing by holding one’s breath. Input into the respiratory control system from higher brain centres may help optimize breathing so that not only are metabolic demands satisfied by breathing but ventilation also is accomplished with minimal use of energy.

Central organization of respiratory neurons

The respiratory rhythm is generated within the pons and medulla oblongata. Three main aggregations of neurons are involved: a group consisting mainly of inspiratory neurons in the dorsomedial medulla, a group made up of inspiratory and expiratory neurons in the ventrolateral medulla, and a group in the rostral pons consisting mostly of neurons that discharge in both inspiration and expiration. It is thought that the respiratory cycle of inspiration and expiration is generated by synaptic interactions within these groups of neurons.

The inspiratory and expiratory medullary neurons are connected to projections from higher brain centres and from chemoreceptors and mechanoreceptors; in turn they drive cranial motor neurons, which govern the activity of muscles in the upper airways and the activity of spinal motor neurons, which supply the diaphragm and other thoracic and abdominal muscles. The inspiratory and expiratory medullary neurons also receive input from nerve cells responsible for cardiovascular and temperature regulation, allowing the activity of these physiological systems to be coordinated with respiration.

Neurally, inspiration is characterized by an augmenting discharge of medullary neurons that terminates abruptly. After a gap of a few milliseconds, inspiratory activity is restarted, but at a much lower level, and gradually declines until the onset of expiratory neuron activity. Then the cycle begins again. The full development of this pattern depends on the interaction of several types of respiratory neurons: inspiratory, early inspiratory, off-switch, post-inspiratory, and expiratory.

Early inspiratory neurons trigger the augmenting discharge of inspiratory neurons. This increase in activity, which produces lung expansion, is caused by self-excitation of the inspiratory neurons and perhaps by the activity of an as yet undiscovered upstream pattern generator. Off-switch neurons in the medulla terminate inspiration, but pontine neurons and input from stretch receptors in the lung help control the length of inspiration. When the vagus nerves are sectioned or pontine centres are destroyed, breathing is characterized by prolonged inspiratory activity that may last for several minutes. This type of breathing, which occasionally occurs in persons with diseases of the brain stem, is called apneustic breathing.

Post-inspiratory neurons are responsible for the declining discharge of the inspiratory muscles that occurs at the beginning of expiration. Mechanically, this discharge aids in slowing expiratory flow rates and probably assists the efficiency of gas exchange. It is thought by some that these post-inspiratory neurons have inhibitory effects on both inspiratory and expiratory neurons and therefore play a significant role in determining the length of the respiratory cycle and the different phases of respiration.

As the activity of the post-inspiratory neurons subsides, expiratory neurons discharge and inspiratory neurons are strongly inhibited. There may be no peripheral manifestation of expiratory neuron discharge except for the absence of inspiratory muscle activity, although in upright humans the lower expiratory intercostal muscles and the abdominal muscles may be active even during quiet breathing. Moreover, as the demand to breathe increases (for example, with exercise), more expiratory intercostal and abdominal muscles contract. As expiration proceeds, the inhibition of the inspiratory muscles gradually diminishes and inspiratory neurons resume their activity.

Chemoreceptors

One way in which breathing is controlled is through feedback by chemoreceptors. There are two kinds of respiratory chemoreceptors: arterial chemoreceptors, which monitor and respond to changes in the partial pressure of oxygen and carbon dioxide in the arterial blood, and central chemoreceptors in the brain, which respond to changes in the partial pressure of carbon dioxide in their immediate environment. Ventilation levels behave as if they were regulated to maintain a constant level of carbon dioxide partial pressure and to ensure adequate oxygen levels in the arterial blood. Increased activity of chemoreceptors caused by hypoxia or an increase in the partial pressure of carbon dioxide augments both the rate and depth of breathing, which restores partial pressures of oxygen and carbon dioxide to their usual levels. On the other hand, too much ventilation depresses the partial pressure of carbon dioxide, which leads to a reduction in chemoreceptor activity and a diminution of ventilation. During sleep and anesthesia, lowering carbon dioxide levels three to four millimetres of mercury below values occurring during wakefulness can cause a total cessation of breathing (apnea).

Peripheral chemoreceptors

Hypoxia, or the reduction of oxygen supply to tissues to below physiological levels (produced, for example, by a trip to high altitudes), stimulates the carotid and aortic bodies, the principal arterial chemoreceptors. The two carotid bodies are small organs located in the neck at the bifurcation of each of the two common carotid arteries into the internal and external carotid arteries. This organ is extraordinarily well perfused and responds to changes in the partial pressure of oxygen in the arterial blood flowing through it rather than to the oxygen content of that blood (the amount of oxygen chemically combined with hemoglobin). The sensory nerve from the carotid body increases its firing rate hyperbolically as the partial pressure of oxygen falls. In addition to responding to hypoxia, the carotid body increases its activity linearly as the partial pressure of carbon dioxide in arterial blood is raised. This arterial blood parameter rises and falls as air enters and leaves the lungs, and the carotid body senses these fluctuations, responding more to rapid than to slow changes in the partial pressure of carbon dioxide. Larger oscillations in the partial pressure of carbon dioxide occur with breathing as metabolic rate is increased. The amplitude of these fluctuations, as reflected in the size of carotid body signals, may be used by the brain to detect changes in the metabolic rate and to produce appropriate adjustment in ventilation.

The carotid body communicates with medullary respiratory neurons through sensory fibres that travel with the carotid sinus nerve, a branch of the glossopharyngeal nerve. Microscopically, the carotid body consists of two different types of cells. The type I cells are arranged in groups and are surrounded by type II cells. The type II cells are generally not thought to have a direct role in chemoreception. Fine sensory nerve fibres are found in juxtaposition to type I cells, which, unlike type II cells, contain electron-dense vesicles. Acetylcholine, catecholamines, and neuropeptides such as enkephalins, vasoactive intestinal polypeptide, and substance P, are located within the vesicles. It is thought that hypoxia and hypercapnia (excessive carbon dioxide in the blood) cause the release of one or more of these neuroactive substances from the type I cells, which then act on the sensory nerve. It is possible to interfere independently with the responses of the carotid body to carbon dioxide and oxygen, which suggests that the same mechanisms are not used to sense or transmit changes in oxygen or carbon dioxide. The aortic bodies located near the arch of the aorta also respond to acute changes in the partial pressure of oxygen, but less well than the carotid body responds to changes in the partial pressure of carbon dioxide. The aortic bodies are responsible for many of the cardiovascular effects of hypoxia.

Central chemoreceptors

Carbon dioxide is one of the most powerful stimulants of breathing. As the partial pressure of carbon dioxide in arterial blood rises, ventilation increases nearly linearly. Ventilation normally increases by two to four litres per minute with each one millimetre of mercury increase in the partial pressure of carbon dioxide. Carbon dioxide increases the acidity of the fluid surrounding the cells but also easily passes into cells and thus can make the interior of cells more acid. It is not clear whether the receptors respond to the intracellular or extracellular effects of carbon dioxide or acidity.

Even if both the carotid and aortic bodies are removed, inhaling gases that contain carbon dioxide stimulates breathing. This observation shows that there must be additional receptors that respond to changes in the partial pressure of carbon dioxide. Current thinking places these receptors near the undersurface (ventral part) of the medulla. However, microscopic examination has not conclusively identified specific chemoreceptor cells in this region. The same areas of the ventral medulla also contain vasomotor neurons that are concerned with the regulation of blood pressure. Some investigators suspect that respiratory responses produced at the ventral medullary surface are direct and are caused by interference with excitatory and inhibitory inputs to respiration from these vasomotor neurons. They further suspect that respiratory chemoreceptors that respond to carbon dioxide are more diffusely distributed in the brain.

Muscle and lung receptors

Receptors in the respiratory muscles and in the lung can also affect breathing patterns. These receptors are particularly important when lung function is impaired, since they can help maintain tidal volume and ventilation at normal levels.

Changes in the length of a muscle affect the force it can produce when stimulated. Generally there is a length at which the force generated is maximal. Receptors, called spindles, in the respiratory muscles measure muscle length and increase motor discharge to the diaphragm and intercostal muscles when increased stiffness of the lung or resistance to the movement of air caused by disease impedes muscle shortening. Tendon organs, another receptor in muscles, monitor changes in the force produced by muscle contraction. Too much force stimulates tendon organs and causes decreasing motor discharge to the respiratory muscles and may prevent the muscles from damaging themselves.

Inflation of the lungs in animals stops breathing by a reflex described by German physiologist Ewald Hering and Austrian physiologist Josef Breuer. The Hering-Breuer reflex is initiated by lung expansion, which excites stretch receptors in the airways. Stimulation of these receptors, which send signals to the medulla by the vagus nerve, shortens inspiratory times as tidal volume (the volume of air inspired) increases, accelerating the frequency of breathing. When lung inflation is prevented, the reflex allows inspiratory time to be lengthened, helping to preserve tidal volume.

There are also receptors in the airways and in the alveoli that are excited by rapid lung inflations and by chemicals such as histamine, bradykinin, and prostaglandins. The most important function of these receptors, however, may be to defend the lung against noxious material in the atmosphere. When stimulated, these receptors constrict the airways and cause rapid shallow breathing, which inhibits the penetration of injurious agents into the bronchial tree. These receptors are supplied, like the stretch receptors, by the vagus nerve. Some of these receptors (called irritant receptors) are innervated by myelinated nerve fibres, others (the J receptors) by unmyelinated fibres. Stimulation of irritant receptors also causes coughing.

Variations in breathing

Exercise

One of the remarkable features of the respiratory control system is that ventilation increases sufficiently to keep the partial pressure of carbon dioxide in arterial blood nearly unchanged despite the large increases in metabolic rate that can occur with exercise, thus preserving acid–base homeostasis. A number of signals arise during exercise that can augment ventilation. Sources of these signals include mechanoreceptors in the exercising limbs; the arterial chemoreceptors, which can sense breath-by-breath oscillations in the partial pressure of carbon dioxide; and thermal receptors, because body temperature rises as metabolism increases. The brain also seems to anticipate changes in the metabolic rate caused by exercise, because parallel increases occur in the output from the motor cortex to the exercising limbs and to respiratory neurons. Changes in the concentration of potassium and lactic acid in the exercising muscles acting on unmyelinated nerve fibres may be another mechanism for stimulation of breathing during exercise. It remains unclear, however, how these various mechanisms are adjusted to maintain acid–base balance.

Sleep

During sleep, body metabolism is reduced, but there is an even greater decline in ventilation so that the partial pressure of carbon dioxide in arterial blood rises slightly and arterial partial pressure of oxygen falls. The effects on ventilatory pattern vary with sleep stage. In slow-wave sleep, breathing is diminished but remains regular, while in rapid eye movement sleep, breathing can become quite erratic. Ventilatory responses to inhaled carbon dioxide and to hypoxia are less in all sleep stages than during wakefulness. Sufficiently large decreases in the partial pressure of oxygen or increases in the partial pressure of carbon dioxide will cause arousal and terminate sleep.

During sleep, ventilation may swing between periods when the amplitude and frequency of breathing are high and periods in which there is little attempt to breathe, or even apnea (cessation of breathing). This rhythmic waxing and waning of breathing, with intermittent periods of apnea, is called Cheyne-Stokes breathing, after the physicians who first described it. The mechanism that produces the Cheyne-Stokes ventilation pattern is unclear, but it may entail unstable feedback regulation of breathing. Similar swings in ventilation sometimes occur in persons with heart failure or with central nervous system disease. In addition, ventilation during sleep may intermittently fall to low levels or cease entirely because of partial or complete blockage of the upper airways. In some individuals, this intermittent obstruction occurs repeatedly during the night, leading to severe drops in the levels of blood oxygenation. The condition, called sleep apnea, occurs most commonly in the elderly, in the newborn, in males, and in the obese. Because arousal is often associated with the termination of episodes of obstruction, sleep is of poor quality, and complaints of excessive daytime drowsiness are common. Snoring and disturbed behaviour during sleep may also occur. In some persons with sleep apnea, portions of the larynx and pharynx may be narrowed by fat deposits or by enlarged tonsils and adenoids, which increase the likelihood of obstruction. Others, however, have normal upper airway anatomy, and obstruction may occur because of discoordinated activity of upper airway and chest wall muscles. Many of the upper airway muscles, like the tongue and laryngeal adductors, undergo phasic changes in their electrical activity synchronous with respiration, and the reduced activity of these muscles during sleep may lead to upper airway closure.

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