Which of these factors can override brainstem control of breathing in an infant

The reader understands the organization and function of the respiratory control system.

• Describes the general organization of the respiratory control system.
• Localizes the centers that generate the spontaneous rhythmicity of breathing.
• Describes the groups of neurons that effect inspiration and expiration.
• Describes the other centers in the brainstem that may influence the spontaneous rhythmicity of breathing.
• Lists the cardiopulmonary and other reflexes that influence the breathing pattern.
• States the ability of the brain cortex to override the normal pattern of inspiration and expiration temporarily.
• Describes the effects of alterations in body oxygen, carbon dioxide, and hydrogen ion levels on the control of breathing.
• Describes the sensors of the respiratory system for oxygen, carbon dioxide, and hydrogen ion concentration.

This spontaneously generated cycle of inspiration and expiration can be modified, altered, or even temporarily suppressed by a number of mechanisms. As shown in Figure 9–1, these include reflexes arising in the lungs, the airways, and the cardiovascular system; information from receptors in contact with the cerebrospinal fluid; and commands from higher centers of the brain such as the hypothalamus, the centers of speech, or other areas in the cortex. The centers that are responsible for the generation of the spontaneous rhythmicity of inspiration and expiration are, therefore, able to alter their activity to meet the increased metabolic demand on the respiratory system during exercise or may even be temporarily superseded or suppressed during speech or breath holding.

Figure 9–1.

Schematic representation of the organization of the respiratory control system. A cycle of inspiration and expiration is automatically established in the medullary respiratory center. Its output represents a final common pathway to the respiratory muscles, except for some voluntary pathways that may go directly from higher centers to the respiratory muscles (dashed line). Reflex responses from chemoreceptors and other sensors may modify the cycle of inspiration and expiration established by the medullary respiratory center.

The output of the respiratory control centers in the brainstem controls breathing via a “final common pathway” consisting of the spinal cord, the innervation of the muscles of respiration such as the phrenic nerves, and the muscles of respiration themselves. Alveolar ventilation is therefore determined by the interval between successive groups of discharges of the respiratory neurons and the innervation of the muscles of respiration, which determines the respiratory rate or breathing frequency, and by the frequency of neural discharges transmitted by individual nerve fibers to their motor units, the duration of these discharges, and the number of motor units activated during each inspiration or expiration, which determine the depth of respiration or the tidal volume. Note that some pathways from the cerebral cortex to the muscles of respiration, such as those involved in voluntary breathing, bypass the medullary respiratory center described later in this chapter and travel directly to the spinal α motorneurons. These are represented by the dashed line in Figure 9–1.

The centers that initiate breathing are located in the reticular formation of the medulla, beneath the floor of the fourth ventricle. If the brainstem of an anesthetized animal is sectioned above this area, as seen in the transection labeled III in Figure 9–2, a pattern of inspiration and expiration is maintained (although it is somewhat irregular) even if all other afferents to this area, including the vagi, are also severed. If the brainstem is transected below this area, as seen in the transection labeled IV in Figure 9–2, breathing ceases. This area, known as the medullary center (or medullary respiratory center), was originally believed to consist of 2 discrete groups of respiratory neurons: the inspiratory neurons, which fire during inspiration and the expiratory neurons, which fire during expiration.

Figure 9–2.

The effects of transections at different levels of the brainstem on the ventilatory pattern of anesthetized animals. Left: A schematic representation of the dorsal surface of the lower brainstem. Right: A schematic representation of the breathing patterns (inspiration is upward) corresponding to the transections with the vagus nerves intact or transected. PRG = pontine respiratory groups; DRG = dorsal respiratory group; VRG = ventral respiratory group. (From Physiology of Respiration by Michael P. Hlastala and Albert J. Berger, copyright © 1996 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.)

Activity of the inspiratory neurons is transmitted to the muscles of inspiration, initiating inspiration; activity of the expiratory neurons is transmitted to the muscles of expiration, initiating expiration. It was thought that when the inspiratory neurons discharged, their activity was conducted to the expiratory neuron pool via collateral fibers and the activity of the expiratory neurons was inhibited. Similarly, when the expiratory neurons discharged, their activity was conducted to the inspiratory neuron pool via collateral fibers, and the activity of the inspiratory neurons was inhibited. The reciprocal inhibition of these 2 opposing groups of neurons was believed to be the source of the spontaneous respiratory rhythmicity. More recent studies of the medullary center have not entirely supported this early hypothesis. Furthermore, because expiration is passive in normal quiet breathing, the expiratory neurons may not discharge unless expiration is active.

There are 2 dense bilateral aggregations of respiratory neurons in the medullary respiratory center known as the dorsal respiratory groups (DRG in Figures 9–2 and 9–3) and the ventral respiratory groups (VRG in Figures 9–2 and 9–3). Inspiratory and expiratory neurons are anatomically intermingled to a greater or lesser extent within these areas, and the medullary center does not consist of a discrete “inspiratory center” and a discrete “expiratory center.”

Figure 9–3.

Location of pontine and medullary respiratory neuron aggregations (dorsal view of the brainstem DRG = dorsal respiratory group; VRG = ventral respiratory group; See text for details).

The Dorsal Respiratory Group

The DRG are located bilaterally in the nucleus of the tractus solitarius (NTS), as shown in Figure 9–3. They consist mainly of inspiratory neurons. These inspiratory neurons project primarily to the contralateral spinal cord. They are the principal initiators of the activity of the phrenic nerves and are therefore responsible for maintaining diaphragmatic activity. Dorsal respiratory group neurons send many collateral fibers to those in the ventral respiratory group, but the ventral respiratory group sends only a few collateral fibers to the dorsal respiratory group, as will be discussed in the next section. Reciprocal inhibition therefore seems an unlikely explanation of spontaneous inspiratory and expiratory rhythmicity.

The NTS is the primary projection site of visceral afferent fibers of the ninth cranial nerve (the glossopharyngeal) and the tenth cranial nerve (the vagus). These nerves carry information about the arterial

There are 2 populations of inspiratory neurons in the DRG: One population, called the I α cells, increase their activity if lung inflation is suppressed; the second population, the I β cells, decrease their activity if lung inflation is suppressed. These cells may play an important role in the Hering-Breuer reflexes described later in this chapter. A third population of cells, the P-cells (pump cells), appear to be interneurons involved in relaying afferent activity from pulmonary stretch receptors.

In summary, the DRG is probably responsible for driving the diaphragm and is probably the initial integrating site for many cardiopulmonary reflexes that affect the respiratory rhythm.

The Ventral Respiratory Group

The VRG are located bilaterally in the retrofacial nucleus, the nucleus ambiguus, the nucleus para-ambigualis, and the nucleus retroambigualis, as shown in Figure 9–3. They consist of both inspiratory and expiratory neurons. The neurons in the nucleus ambiguus are primarily vagal motorneurons that innervate the ipsilateral laryngeal, pharyngeal, and tongue muscles involved in breathing and in maintaining the patency of the upper airway. Neurons in the nucleus para-ambigualis mainly innervate contralateral inspiratory muscles, including the external intercostals. In the nucleus retroambigualis, the inspiratory cells appear to be located more rostrally and the expiratory cells are located more caudally. There appear to be 2 populations of inspiratory cells in the nucleus retroambigualis: One group mainly projects contralaterally to external intercostal muscles, with some fibers also sent to the phrenic nerves, thus innervating the diaphragm; the second group appears to project only within the medulla to other inspiratory and expiratory cells. The expiratory neurons in the nucleus retroambigualis project to the contralateral spinal cord to drive the internal intercostal and abdominal muscles. The retrofacial nucleus, located most rostrally in the VRG, mainly contains expiratory neurons in a group of cells called the Bötzinger complex. This group of neurons has been shown to inhibit inspiratory cells in the DRG, as well as some phrenic motorneurons.

In summary, the VRG neurons consist of both inspiratory and expiratory cells. Their major function is to drive either spinal respiratory neurons, innervating mainly the intercostal and abdominal muscles, or the auxiliary muscles of respiration innervated by the vagus nerves. Many expiratory cells may not fire at all during the passive expirations seen in eupneic breathing (see Chapter 2); those that do discharge do not cause contraction of the expiratory muscles.

The mechanism and precise location of the generation of the inspiratory-expiratory cycle, the respiratory rhythm generator, is not firmly established. It may be generated by a network of neurons in the ventral medulla or cells in the pre-Bötzinger complex (Figure 9–3) may act as pacemakers of the respiratory rhythm.

The “Apneustic Center”

If the brainstem is transected in the pons at the level denoted by the line labeled II in Figure 9–2, a breathing pattern called apneusis results if the vagus nerves have also been transected. Apneustic breathing consists of prolonged inspiratory efforts interrupted by occasional expirations. Afferent information that reaches this so-called apneustic center via the vagus nerves must be important in preventing apneusis because apneusis does not occur if the vagus nerves are intact, as shown in Figure 9–2.

Apneusis is probably caused by a sustained discharge of medullary inspiratory neurons. Therefore, the apneustic center may be the site of the normal “inspiratory cutoff switch”; that is, it is the site of projection and integration of various types of afferent information that can terminate inspiration. Apneusis is a result of the inactivation of the inspiratory cutoff mechanism. The specific group of neurons that function as the apneustic center has not been identified, but it must be located somewhere between the lines labeled II and III in Figure 9–2.

If the brainstem is transected immediately caudal to the inferior colliculus, as denoted by the line labeled I in Figure 9–2, the breathing pattern shows an essentially normal balance between inspiration and expiration, even if the vagus nerves are transected. As discussed in the previous section, transections made caudal to the line labeled II in Figure 9–2 lead to apneusis in the absence of the vagus nerves. A group of respiratory neurons known as the pontine respiratory groups, (formerly called the pneumotaxic center) therefore function to modulate the activity of the apneustic center. These cells, located in the upper pons in the nucleus parabrachialis medialis and the Kölliker-Fuse nucleus (shown in Figure 9–3), probably function to “fine-tune” the breathing pattern. Electrical stimulation of these structures can result in synchronization of phrenic nerve activity with the stimulus or premature switching from inspiration to expiration and vice versa. Pulmonary inflation afferent information can inhibit the activity of the pontine respiratory groups, which may in turn act to modulate the threshold for lung inflation inspiratory cutoff. The pontine respiratory groups may also modulate the respiratory control system’s response to other stimuli, such as hypercapnia and hypoxia.

Axons projecting from the DRG, the VRG, the cortex, and other supraspinal sites descend in the spinal white matter to activate the diaphragm and the intercostal and abdominal muscles of respiration, as already discussed. There is also integration of descending influences and local spinal reflexes that can affect these respiratory motor neurons. Descending axons with inspiratory activity excite phrenic and external intercostal motorneurons and also inhibit internal intercostal motorneurons by exciting spinal inhibitory interneurons. They are actively inhibited during expiratory phases of the respiratory cycle.

Ascending pathways in the spinal cord, carrying information from pain, touch, and temperature receptors, as well as from proprioceptors, can also influence breathing, as will be discussed in the next section. Inspiratory and expiratory fibers appear to be separated in the spinal cord.

A large number of sensors located in the lungs, the cardiovascular system, the muscles and tendons, and the skin and viscera can elicit reflex alterations in the control of breathing. These are summarized in Table 9–1.

Table 9–1. Reflex Mechanisms of Respiratory Control

View Table||Download (.pdf)

Table 9–1. Reflex Mechanisms of Respiratory Control

Respiratory Reflexes Arising from Pulmonary Stretch Receptors

Three respiratory reflexes can be elicited by stimulation of the pulmonary stretch receptors: the Hering-Breuer inflation reflex, the Hering-Breuer deflation reflex, and the “paradoxical” reflex of Head.

The Hering-Breuer Inflation Reflex

In 1868, Breuer and Hering reported that a maintained distention of the lungs of anesthetized animals decreased the frequency of the inspiratory effort or caused a transient apnea. The stimulus for this reflex is pulmonary inflation. The sensors are stretch receptors located within the smooth muscle of large and small airways. They are sometimes referred to as slowly adapting pulmonary stretch receptors because their activity is maintained with sustained stretches. The afferent pathway consists of large myelinated fibers in the vagus; as mentioned previously, these fibers appear to enter the brainstem and project to the DRGs, the apneustic center, and the pontine respiratory groups. The efferent limb of the reflex consists of bronchodilation in addition to the apnea or slowing of the ventilatory frequency (due to an increase in the time spent in expiration) already mentioned. Lung inflation also causes reflex effects in the cardiovascular system: Moderate lung inflations cause an increase in heart rate and may cause a slight vasoconstriction; very large inflations may cause a decrease in heart rate and systemic vascular resistance.

The Hering-Breuer inflation reflex was originally believed to be an important determinant of the rate and depth of ventilation. Vagotomized anesthetized animals breathe much more deeply and less frequently than they did before their vagus nerves were transected. It was therefore assumed that the Hering-Breuer inflation reflex acts tonically to limit the tidal volume and establish the depth and rate of breathing. More recent studies on unanesthetized humans have cast doubt on this conclusion because the central threshold of the reflex is much higher than the normal tidal volume during eupneic breathing. Tidal volumes of 800 to 1500 mL are generally required to elicit this reflex in conscious eupneic adults. The Hering-Breuer inflation reflex may help minimize the work of breathing by inhibiting large tidal volumes (see Chapter 2) as well as to prevent overdistention of the alveoli at large volumes. It may also be important in the control of breathing in babies. Infants have Hering-Breuer inflation reflex thresholds within their normal tidal volume ranges, and the reflex may be an important influence on their tidal volumes and respiratory rates.

The Hering-Breuer Deflation Reflex

Breuer and Hering also noted that abrupt deflation of the lungs increases the ventilatory rate. This could be a result of decreased stretch receptor activity or of stimulation of other pulmonary receptors, or rapidly adapting receptors such as the irritant receptors and J receptors, which will be discussed later in this chapter. The afferent pathway is the vagus, and the effect is hyperpnea. This reflex may be responsible for the increased ventilation elicited when the lungs are deflated abnormally, as in pneumothorax, or it may play a role in the periodic spontaneous deep breaths (“sighs”) that help prevent atelectasis. These sighs occur occasionally (approximately 6–8/hour) and irregularly during the course of normal, quiet, spontaneous breathing. They consist of a slow deep inspiration (larger than a normal tidal volume) followed by a slow expiration. This response appears to be very important because patients maintained on mechanical ventilators must be given large tidal volumes or periodic deep breaths or they develop diffuse atelectasis, which may lead to arterial hypoxemia. Yawns may also help prevent atelectasis, although there is no consensus on how they are initiated.

The Hering-Breuer deflation reflex may be very important in helping to actively maintain infants’ functional residual capacities (FRCs). It is very unlikely that infants’ FRCs are determined passively like those of adults because the inward recoil of their lungs is considerably greater than the outward recoil of their very compliant chest walls.

The Paradoxical Reflex of Head

In 1889, Henry Head performed experiments designed to show the effects of the Hering-Breuer inflation reflex on the control of breathing. Instead of transecting the vagus nerves, he decided to block their function by cooling them to 0°C. As he rewarmed the vagus nerves, he noted that in the situation of a selective partial block of the vagus nerves, lung inflation caused a further inspiration instead of the apnea expected when the vagus nerves were completely functional. The receptors for this paradoxical reflex are located in the lungs, but their precise location is not known. Afferent information travels in the vagus; the effect is very deep inspirations. This reflex may also be involved in the sigh response, or it may be involved in generating the first breath of the newborn baby; very great inspiratory efforts must be generated to inflate the fluid-filled lungs.

Respiratory Reflexes Arising from Receptors in the Airways and the Lungs

The Pharyngeal Dilator Reflex

As discussed in Chapter 2, negative pressure in the upper airway causes reflex contraction of the pharyngeal dilator muscles. The receptors appear to be located in the nose, mouth, and upper airways; the afferent pathways appear to be in the trigeminal, laryngeal, and glossopharyngeal nerves. This reflex may be very important in protecting the upper airways from collapsing, especially during sleep (See Chapter 11). Inhibition or interference with this reflex may be one of the causes of obstructive sleep apnea.

Irritant Receptors

Mechanical or chemical irritation of the airways (and possibly the alveoli) can elicit a reflex cough or sneeze, or it can cause hyperpnea, bronchoconstriction, and increased blood pressure. The receptors are located in the nasal mucosa, upper airways, tracheobronchial tree, and possibly the alveoli themselves. Those in the larger airways of the tracheobronchial tree, which also respond to stretch, are sometimes referred to as rapidly adapting pulmonary stretch receptors because their activity decreases rapidly during a sustained stimulus. The afferent pathways are the vagus nerves for all but the receptors located in the nasal mucosa, which send information centrally via the trigeminal and olfactory tracts. The cough and the sneeze reflexes are discussed in greater detail in Chapter 10.

Respiratory Reflexes Arising from Pulmonary Vascular Receptors (J Receptors)

Pulmonary embolism causes apnea or rapid shallow breathing (tachypnea); pulmonary vascular congestion causes tachypnea. Injection of chemicals such as phenyldiguanide and capsaicin into the pulmonary circulation may also elicit apnea or rapid shallow breathing. The receptors responsible for initiating these responses are located in the walls of the pulmonary capillaries or in the interstitium; therefore, they are called J (for juxtapulmonary-capillary) receptors. Stimulation of these receptors by pulmonary vascular congestion or an increase in pulmonary interstitial fluid volume leads to tachypnea; decreased stimulation of the receptors caused by pulmonary emboli obstructing vessels proximal to the capillaries leads to decreased ventilation. In addition, these receptors might be responsible for the dyspnea (a feeling of difficult or labored breathing) encountered during the pulmonary vascular congestion and edema secondary to left ventricular failure or even the dyspnea that healthy people feel at the onset of exercise. The afferent pathway of these reflexes is slow-conducting nonmyelinated vagal fibers. Other possible causes of dyspnea include stimulation of receptors in the left and right atria, the right ventricle, or the pulmonary artery by increased pressure or stretch; stimulation of muscle spindles in the respiratory muscles by “length-tension inappropriateness”; stimulation of the carotid bodies by hypoxemia, hypercapnia, and acidosis and stimulation of the central chemoreceptors by hypercapnia or acidosis (discussed later in this chapter); stimulation of receptors in the extremities; or by psychological reasons.

Respiratory Reflexes Arising from the Cardiovascular System

The arterial chemoreceptors, and to a much lesser extent the arterial baroreceptors, can exert a great influence on the respiratory control system. The role of the arterial chemoreceptors in the control of ventilation will be discussed in greater detail in subsequent sections of this chapter and will only be briefly summarized here.

Arterial Chemoreceptors

The arterial chemoreceptors are located bilaterally in the carotid bodies, which are situated near the bifurcations of the common carotid arteries, and in the aortic bodies, which are located in the arch of the aorta. They respond to low arterial

Arterial Baroreceptors

The arterial baroreceptors exert a minor influence on the control of ventilation. Baroreceptors are stretch receptors that are responsive to changes in pressure. They are located in the carotid sinuses, which are situated at the origin of the internal carotid arteries near the bifurcation of the common carotid arteries, and in the aortic arch. The afferent pathways are Hering’s nerve and the glossopharyngeal nerve for the carotid baroreceptors and the vagus nerve for the aortic baroreceptors. The effects of stimulation of the arterial baroreceptors by elevated blood pressure are a brief apnea and bronchodilation.

Respiratory Reflexes Arising from Muscles and Tendons

Stimulation of receptors located in the muscles, the tendons, and the joints can increase ventilation. Receptors in the muscles of respiration (eg, muscle spindles) and rib cage may play an important role in adjusting the ventilatory effort to elevated workloads and may help minimize the work of breathing. Receptors in the joints and muscles may also participate in initiating and maintaining the elevated ventilation that occurs during exercise, as will be discussed later in this chapter. Afferent information ascends to the respiratory controller via the spinal cord, as mentioned previously in this chapter.

Reflex Respiratory Responses to Pain

Somatic pain generally causes hyperpnea; visceral pain generally causes apnea or decreased ventilation.

The spontaneous rhythmicity generated in the medullary respiratory center can be completely overwhelmed (at least temporarily) by influences from higher brain centers. In fact, the greatest minute ventilations obtainable from healthy conscious human subjects can be attained voluntarily, exceeding those obtained with the stimuli of strenuous exercise, hypercapnia, or hypoxia. This is the underlying concept of the maximum voluntary ventilation (MVV) test sometimes used to assess the respiratory system. Conversely, the respiratory rhythm can be completely suppressed for several minutes by voluntary breath holding, until the chemical drive to respiration (high

During speech, singing, or playing a wind instrument, the normal cycle of inspiration and expiration is automatically modified by higher brain centers. In certain emotional states, chronic hyperventilation severe enough to cause respiratory alkalosis may occur, as was discussed in Chapter 8.

The respiratory control system normally reacts very effectively to alterations in the internal “chemical” environment of the body. Changes in the body

The arterial and cerebrospinal fluid partial pressures of carbon dioxide are probably the most important inputs to the ventilatory control system in establishing the breath-to-breath levels of tidal volume and ventilatory frequency. (Of course, changes in carbon dioxide lead to changes in hydrogen ion concentration, and so the effects of these 2 stimuli can be difficult to separate.) An elevated level of carbon dioxide is a very powerful stimulus to ventilation: Only voluntary hyperventilation and the hyperpnea of exercise can surpass the minute ventilations obtained with hypercapnia. However, the arterial

Acutely increasing the levels of carbon dioxide in the inspired air (the

The physiologic response to elevated carbon dioxide is dependent on its concentration. Low concentrations of carbon dioxide in the inspired air are easily tolerated, with an increase in ventilation the main effect. Greater levels cause dyspnea, severe headaches secondary to the cerebral vasodilation caused by the elevated

The ventilatory response of a normal conscious person to physiologic levels of carbon dioxide is shown in Figure 9–4.

Figure 9–4.

Ventilatory carbon dioxide response curves at 3 different levels of arterial

Figure 9–4 also shows that hypoxia potentiates the ventilatory response to carbon dioxide. At lower arterial

Other influences on the carbon dioxide response curve are illustrated in Figure 9–5. Sleep (see Chapter 11 for more on sleep and the respiratory system.) shifts the curve slightly to the right. The arterial

Figure 9–5.

The effects of sleep, narcotics, chronic obstructive pulmonary disease, deep anesthesia, and metabolic acidosis on the ventilatory response to carbon dioxide.

Chronic obstructive lung diseases depress the ventilatory response to hypercapnia, in part because of depressed ventilatory drive secondary to central acid-base changes, and because the work of breathing may be so great that ventilation cannot be increased normally. Metabolic acidosis displaces the carbon dioxide response curve to the left, indicating that for any particular

As already discussed, the respiratory control system constitutes a negative-feedback system. This is exemplified by the response to carbon dioxide. Increased metabolic production of carbon dioxide increases the carbon dioxide brought to the lung. If alveolar ventilation stayed constant, the alveolar

Figure 9–6.

Curve A: The effect of ventilation on the arterial

The curve labeled A in Figure 9–6 shows the effect of increasing ventilation (here

As can be seen in Figure 9–7, the respiratory control system constitutes a negative-feedback system, with the

Figure 9–7.

Negative-feedback control systems. A: General scheme of a negative-feedback control system. B: How the respiratory control system works as a negative-feedback control system. Note that the central chemoreceptors also act as sensors for the respiratory control system, with the

Peripheral Chemoreceptors

The peripheral chemoreceptors (also called the arterial chemoreceptors) increase their firing rate in response to increased arterial

The response of the arterial chemoreceptors changes nearly linearly with the arterial

Central Chemoreceptors

The central chemoreceptors are exposed to the cerebrospinal fluid and are not in direct contact with the arterial blood. As shown in Figure 9–8, the cerebrospinal fluid is separated from the arterial blood by the blood-brain barrier. Carbon dioxide can easily diffuse through the blood-brain barrier, but hydrogen ions and bicarbonate ions do not. Because of this, alterations in the arterial

Figure 9–8.

Representation of the central chemoreceptor showing its relationship to carbon dioxide (CO2), hydrogen (H+), and bicarbonate (

The composition of the cerebrospinal fluid is considerably different from that of the blood. It is formed mainly in the choroid plexus of the lateral ventricles. Enzymes, including carbonic anhydrase, play a large role in cerebrospinal fluid formation: The cerebrospinal fluid is not merely an ultrafiltrate of the plasma. CSF is continuously produced, mainly in the choroid plexuses, and reabsorbed in the arachnoid villi; it is estimated to turn over 3 to 5 times per day. The pH of the cerebrospinal fluid is normally about 7.32, compared with the pH of 7.40 of arterial blood. The

The central chemoreceptors respond to local increases in hydrogen ion concentration or

The relative contributions of the peripheral and central chemoreceptors in the ventilatory response to elevated carbon dioxide levels are dependent on the time frame considered. Animals experimentally deprived of the afferent fibers from the arterial chemoreceptors and patients with surgically removed carotid bodies show about 60% to 90% of the normal total steady-state response to elevated inspired carbon dioxide concentrations delivered in hyperoxic gas mixtures, indicating that the peripheral chemoreceptors contribute only 10% to 40% of the steady-state response. Other studies performed on normoxic men indicate that up to one third or one half of the onset of the response can come from the arterial chemoreceptors when rapid changes in arterial

Recent investigations have implicated other sensors for carbon dioxide in the body that may influence the control of ventilation. Chemoreceptors within the pulmonary circulation or airways have been proposed but have not as yet been substantiated or localized.

Figure 9–9.

The ventilatory response to increased plasma hydrogen ion concentration.

Table 9–2. Effects of Metabolic Acidosis (of Nonbrain Origin) on Arterial and Central Chemoreceptor Ventilatory Drive

Similar mechanisms must alter the bicarbonate concentration in the cerebrospinal fluid in the chronic respiratory acidosis of chronic obstructive lung disease because the pH of the cerebrospinal fluid is nearly normal. In this case the cerebrospinal fluid concentration of bicarbonate increases nearly proportionately to its increased concentration of carbon dioxide.

The ventilatory response to hypoxia arises solely from the peripheral chemoreceptors. The carotid bodies are much more important in this response than are the aortic bodies, which are not capable of sustaining the ventilatory response to hypoxia by themselves. In the absence of the peripheral chemoreceptors, the effect of increasing degrees of hypoxia is a progressive direct depression of the central respiratory controller. Therefore, when the peripheral chemoreceptors are intact, their excitatory influence on the central respiratory controller must offset the direct depressant effect of hypoxia.

The response of the respiratory system to hypoxia is shown in Figure 9–10.

Figure 9–10.

The ventilatory responses to hypoxia at 3 different levels of arterial

Experiments have shown that the respiratory response to hypoxia is related to the change in

Hypoxia alone, by stimulating alveolar ventilation, causes a decrease in arterial

Exercise increases oxygen consumption and carbon dioxide production; the ventilatory control system must adjust to meet these increased demands. Minute ventilation increases with the level of exercise; it increases linearly with both oxygen consumption and carbon dioxide production up to a level of about 60% of the subject’s maximal work capacity. Above that level, minute ventilation increases faster than oxygen consumption but continues to rise proportionally to the increase in carbon dioxide production. This increase in ventilation above oxygen consumption at high work levels is caused by the increased lactic acid production that occurs as a result of anaerobic metabolism. The hydrogen ions liberated in this process can stimulate the arterial chemoreceptors directly; the buffering of hydrogen ions by bicarbonate ions also results in production of carbon dioxide in addition to that derived from aerobic metabolism.

The ventilatory response to constant work-rate exercise consists of 3 or 4 phases, as shown in Figure 9–11. At the beginning of exercise there is an immediate increase in ventilation (Phase I). This is followed by a phase of slowly increasing ventilation (Phase II), ultimately rising to a final steady-state phase if the exercise is not too severe (Phase III). The initial immediate increase in ventilation may constitute as much as 50% of the total steady-state response, although it is usually a smaller fraction of the total.

Figure 9–11.

The time course of changes in ventilation in relation to a short period of moderate exercise. Note the instant increase in ventilation (Phase I) at the start of exercise before the metabolic consequences of exercise have had time to develop.

The increase in minute ventilation is usually a result of increases in both tidal volume and breathing frequency. Initially, the tidal volume increases more than the rate, but as metabolic acidosis develops, the increase in breathing frequency predominates.

The mechanisms by which exercise increases minute ventilation remain controversial. They are summarized in Table 9–3. No single factor can fully account for the ventilatory response to exercise, and much of the response is unexplained. The immediate increase in ventilation occurs too quickly to be a response to alterations in metabolism or changes in the blood gases. This “neural component” partly consists of collateral fibers to the respiratory muscles from the motor cortex neurons innervating the exercising skeletal muscles and may also be partly accounted for by a conditioned reflex, that is, a learned response to exercise. Experiments have also demonstrated that input to the respiratory centers from proprioceptors located in the joints and muscles of the exercising limbs may play a large role in the ventilatory response to exercise. Passive movements of the limbs of anesthetized animals or conscious human subjects cause an increase in ventilation. The ventilatory and cardiovascular responses to exercise may be coordinated (and in part initiated) in an “exercise center” in the hypothalamus.

Table 9–3. Ventilatory Response to Exercise

The arterial chemoreceptors do not appear to play a role in the initial immediate ventilatory response to exercise. In mild or moderate exercise (that below the point at which anaerobic metabolism plays a role in energy supply), mean arterial

Several investigators have suggested that there may be receptors in the pulmonary circulation that could respond to an increased carbon dioxide load in the mixed venous blood or in the heart that could respond to the increased cardiac output or increased cardiac work. Others have proposed that receptors in the exercising muscles that respond to mechanical stresses or the metabolites released during exercise, some of which can stimulate pain receptors (nociceptors), may send information about the increased muscle metabolism to the respiratory controllers. Thus far, these “mixed venous chemoreceptors” and “metaboreceptors” have not been demonstrated conclusively. The increase in body temperature that occurs during exercise may also contribute to the ventilatory response.

From Raff H, Levitzky MG, eds. Medical Physiology: A Systems Approach. New York: McGraw-Hill; 2011:394.

A 14-year-old girl forgot her prescription drug on a weekend sleepover party at her friend’s house. She arrives in the emergency department lethargic, confused, and disoriented. She has vomited twice and says she is thirsty and her stomach hurts. The symptoms developed gradually overnight. Her heart rate is 110/min, her blood pressure is 95/75 mm Hg, and her respiratory rate is 22/min with obvious large tidal volumes. Her blood glucose is very high at 450 mg/dL, her arterial

The patient has type 1 diabetes mellitus; she is in diabetic ketoacidosis. The drug she did not bring with her is insulin; as a result her blood glucose concentration is very high and she is producing ketone bodies. Nausea, vomiting, abdominal pain, and confusion are common symptoms and signs of diabetes mellitus. Hydrogen ions from the ketone bodies, which are acids, have been buffered by bicarbonate and have been exhaled as carbon dioxide, explaining the low bicarbonate concentration and the elevated anion gap (see Chapter 8). The hydrogen ions are stimulating her arterial chemoreceptors causing her to hyperventilate, as shown by her low arterial

Berger AJ. Control of breathing. In: Murray JF, Nadel JA, eds Textbook of Respiratory Medicine. 3rd ed. Philadelphia, Pa: WB Saunders and Company; 2000:179–196.

Berger AJ, Mitchell RA, Severinghaus JW. Regulation of respiration. N Engl J Med. 1977;297:92–97, 138–143, 194–201.  [PubMed: 865581]

Blain GM, Smith CA, Henderson KS, Dempsey JA. Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog. J Appl Physiol. 2009;106:1564–1573.  [PubMed: 19246650]

Cherniack NS, Coleridge JCG. Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu Rev Physiol. 1994;56:69–91.

Comroe JH Jr. Physiology of Respiration. 2nd ed. Chicago, Ill: Year Book; 1974:22–93.

Duffin J. Role of acid-base balance in the chemoreflex control of breathing. J Appl Physiol. 2005;99:2255–2265.  [PubMed: 16109829]

Duffin J, Phillipson EA. Hypoventilation and hyperventilation syndromes. In: Mason RJ, Broaddus VC, Martin TR, et al. eds. Murray & Nadel’s Textbook of Respiratory Medicine. 5th ed. Philadelphia, Pa: WB Saunders and Company; 2010:1859–1880.

Eldridge FL. Central integration of mechanisms in exercise hyperpnea. Med Sci Sports Exerc. 1994;26:319–327.  [PubMed: 8183096]

Fidone SJ, Gonzalez C. Initiation and control of chemoreceptor activity in the carotid body. Compr Physiol 2011, Supplement 11: Handbook of Physiology, The Respiratory System, Control of Breathing: 247–312. First published in print 1986. doi: 10.1002/cphy.cp030209

Hannam S, Ingram DM, Rabe-Hesketh S, Milner AD. Characterisation of the Hering-Breuer deflation reflex in the human neonate. Respir Physiol. 2000;124:51–64.

Hassan A, Gossage J, Ingram D, Lee S, Milner AD. Volume of activation of the Hering-Breuer inflation reflex in the newborn infant. J Appl Physiol. 2001;90:763–769.  [PubMed: 11181581]

Hlastala MP, Berger AJ. Physiology of Respiration. 2nd ed. New York, NY: Oxford University Press; 2001:134–147.

Kazemi H, Johnson DC. Regulation of cerebrospinal fluid acid-base balance. Physiol Rev. 1986;66:953–1037.  [PubMed: 2429339]

Lumb AB. Nunn’s Applied Respiratory Physiology. 7th ed. London: Churchill Livingstone; 2011:61–82.

Mahamed S, Ali AF, Ho D, Wang B, Duffin J. The contribution of chemoreflex drives to resting breathing in man. Exp Physiol. 2001;86.1:109–116.

Mateika JH, Duffin J. A review of the control of breathing during exercise. Eur J Appl Physiol. 1995;71:1–27.  [PubMed: 7556128]

Nattie E. Why do we have both peripheral and central chemoreceptors? J Appl Physiol. 2006;100:9–10.  [PubMed: 16357079]

Nattie E. Julius Comroe Jr. Distinguished lecture: central chemoreception: then…and now. J Appl Physiol. 2011;110:1–8.  [PubMed: 21071595]

Paintal AS. Sensations from J receptors. News Physiol Sci. 1995;10:238–243.

Pien GW, Pack AI. Sleep-disordered breathing. In: Mason RJ, Broaddus VC, Martin TR, eds. Murray & Nadel’s Textbook of Respiratory Medicine. 5th ed. Philadelphia, PA: WB Saunders and Company; 2010:1881–1913.

Rabbette PS, Stocks J. Influence of volume dependency and timing of airway occlusions on the Hering-Breuer reflex in infants. J Appl Physiol. 1998;85:2033–2039.  [PubMed: 9843523]

Rekling JC, Feldman JL. Pre Bötzinger complex and pacemaker neurons: Hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol. 1998;60:385–405.  [PubMed: 9558470]

Shea SA. Life without ventilatory chemosensitivity. Respir Physiol. 1997;110:199–210.  [PubMed: 9407612]

Schwab RJ, Goldberg AN, Pack AI. Sleep apnea syndromes. In: Fishman AP, ed. Pulmonary Diseases and Disorders. 3rd ed. New York, NY: McGraw-Hill; 1998:1617–1637.

Von Euler C. Brain stem mechanisms for generation and control of breathing pattern. Compr Physiol 2011, Supplement 11: Handbook of Physiology, The Respiratory System, Control of Breathing: 1–67. First published in print 1986. doi: 10.1002/cphy.cp030201

Wasserman K. Breathing during exercise. N Engl J Med. 1978;298:780–785.  [PubMed: 628413]

Wasserman K, Casaburi R. Dyspnea: Physiological and pathophysiological mechanisms. Annu Rev Med. 1988;39:503–515.  [PubMed: 3285788]

Weir EK, Lopez-Barneo J, Buckler KJ, et al. Acute oxygen-sensing mechanisms. N Engl J Med. 2005; 353:2042–2055.  [PubMed: 16282179]

Wenninger JM, Pan LG, Klum L, et al. Large lesions in the pre-Boetzinger complex area eliminate eupneic respiratory rhythm in awake goats. J Appl Physiol. 2004;97:1629–1636.  [PubMed: 15247161]

What factors can override brainstem control of breathing in an infant pals?

Which of the following are most commonly associated with disordered control of breathing?

Which interventions may be included in the management of disordered control of breathing due to increased intracranial pressure?

Which part of the brain triggers inspiration?