Anatomic and Physiologic Aspects of Neural, Muscular, and Chest Wall Interactions with the Lungs

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Anatomic and Physiologic Aspects of Neural, Muscular, and Chest Wall Interactions with the Lungs

RESPIRATORY CONTROL

Organization of Respiratory Control

Ventilatory Response to Hypercapnia and Hypoxia

Ventilatory Response to Other Stimuli

RESPIRATORY MUSCLES

Movement of gas into and out of the lungs requires the action of a pump capable of creating negative intrathoracic pressure, expanding the lungs, and initiating airflow with each inspiration. This pumplike action is provided by the respiratory muscles, including the diaphragm, working in conjunction with the chest wall. However, the muscles themselves have no intrinsic rhythmic activity in the way cardiac muscle does; they must be driven by rhythmic impulses provided by a “controller.”

This chapter focuses on the anatomic and physiologic features of the controlling system and the respiratory muscles to provide background for the discussion in Chapters 18 and 19. Those chapters discuss disorders affecting respiratory control, respiratory musculature, and the chest wall. Although much of the physiology and many of the clinical problems discussed here and in the next two chapters do not directly involve the lungs, they are so closely intertwined with respiratory function and dysfunction that they are appropriately considered in a textbook of pulmonary disease.

Respiratory Control

Although the process of breathing is a normal rhythmic activity that occurs without conscious effort, it involves an intricate controlling mechanism at the level of the central nervous system (CNS). The CNS transmits signals to the respiratory muscles, initiating inspiration approximately 12 to 20 times per minute. Remarkably, this controlling system is normally able to respond to varied needs of the individual, appropriately increasing ventilation during exercise and maintaining arterial blood gases within a narrow range.

This section begins with a description of the structural organization of neural control of ventilation and proceeds to a consideration of how various stimuli may interact with and adjust the output of the respiratory controller. The ways the output of the controller can be quantified and how these techniques have proved useful in evaluating patients with a variety of clinical disorders are briefly discussed.

Organization of Respiratory Control

The basic organization of the respiratory control system is shown in Figure 17-1. Crucial to this system is the CNS “generator.” Signals that originate from the generator travel down the spinal cord to the various respiratory muscles. The inspiratory muscles, the most important of which is the diaphragm, respond to the signals by contracting and initiating inspiration. This process is described later in more detail under Respiratory Muscles.

Figure 17-1 Schematic diagram shows organization of respiratory control system. Dashed lines show feedback loops affecting respiratory generator.

As a result of inspiratory muscular contraction, the diaphragm descends, the chest wall expands, and air flows down a pressure gradient from the mouth through the tracheobronchial tree to the alveolar spaces. Gas exchange in the distal parenchyma allows movement of O₂ into the blood and release of CO₂ from the blood into gas within the alveoli.

Although this sequence of events sounds relatively straightforward, it is complicated by an intricate feedback system that adjusts the output of the generator to achieve the desired effect. If the response of the respiratory muscles to the generator’s signal is inadequate, as judged by a variety of respiratory “reflexes,” the generator increases its output to compensate for the lack of expected effect. If the arterial blood gases deviate from the desired level, chemosensors for O₂ and CO₂ alter their input to the respiratory generator, ultimately affecting its output. In addition, input from other regions of the CNS, particularly the cerebral cortex and pons, can adjust the generator’s net output.

The Respiratory Generator

Considering the importance of the respiratory generator in this scheme of respiratory control, its anatomy and mode of action are described here. Much of the work clarifying the location of the respiratory generator involved animal experiments with transections at various levels of the CNS and assessment of the effects on ventilation. Because transection between the brain and brainstem does not significantly alter ventilation, the generator apparently resides somewhere at the level of the brainstem or lower and does not require interaction with higher cortical centers. When transections are made at various points within the brainstem, the breathing pattern is substantially altered, but ventilation is not eliminated. Only when a transection is made between the medulla and the spinal cord does ventilation cease, indicating that the respiratory generator resides within the medulla.

A central respiratory generator within the medulla controls activity of the respiratory muscles.

Although the respiratory center (or generator) has been referred to as a single region, it appears that more than one network of neurons within the medulla is involved in initiating and coordinating respiratory activity. According to a popular model, one group of neurons is responsible for initiating inspiration and regulating its speed as a result of the intensity of neuronal activity; another group of neurons controls “switching off” inspiration and hence determines the onset of expiration.

Therefore, there are two aspects of ventilatory control: (1) the degree of inspiratory drive or central inspiratory activity (which regulates the inspiratory flow rate), and (2) the timing mechanism (which controls the termination of inspiration). These two determining factors act in concert to set the respiratory rate and tidal volume and thus the minute ventilation and specific pattern of breathing.

Input from Other Regions of the Central Nervous System

Even though the medullary respiratory center does not require additional input to drive ventilation, it does receive other information that contributes to a regular pattern of breathing and more precise ventilatory control. For example, input from the pons appears to be necessary for a normal, coordinated breathing pattern. When the influence of the pons is lost, irregularities in the breathing pattern ensue.

In addition to pathways involved in the “automatic” or involuntary control of ventilation, the cerebral cortex exerts a conscious or voluntary control over ventilation. Cortical overriding of automatic control can be seen with either voluntary breath holding or hyperventilation. Its usefulness is readily apparent in a person’s need for voluntary control of breathing during such activities as speaking, eating, and swimming. Interestingly, the automatic control of ventilation may be disturbed while conscious control remains intact. In these cases, during wakefulness the cerebral cortex exerts sufficient voluntary control over ventilation to maintain normal arterial blood gas values. During periods when the patient is dependent on automatic ventilatory control (e.g., during sleep), marked hypoventilation or apnea may occur. This rare condition, called congenital central hypoventilation syndrome, has also been known as Ondine’s curse, after a mythologic tale in which the suitor of Neptune’s daughter was cursed to lose automatic control over all bodily functions when he fell asleep. Defects in the PHOX2b gene mapped to chromosome 4p12 have been identified in most cases. PHOX2b encodes a highly conserved domain for transcription factors important in neural development. Further research into the pathogenesis of this condition undoubtedly will lead to better understanding of the mechanisms of normal ventilatory control.

Chemoreceptors

Maintenance of arterial blood gases is the ultimate goal of ventilatory control, and an important feedback loop adjusts respiratory center output if blood gases are not maintained at the appropriate level (see Fig. 17-1). Elevation of PCO₂ (hypercapnia) and depression of PO₂ (hypoxemia) both are capable of stimulating ventilation. In each case, one or more chemoreceptors detect alterations in PCO₂ or PO₂ and accordingly vary their input to the medullary respiratory center.

Changes in PCO₂ are sensed primarily at a central chemoreceptor in the medulla.

The primary sensor for CO₂ is located near the ventrolateral surface of the medulla and is called the central chemoreceptor. Even though it is located in the medulla, the central chemoreceptor is clearly separate from the medullary respiratory center and should not be confused with it. The central chemoreceptor does not appear to respond directly to blood PCO₂ but rather to the pH of the extracellular fluid (ECF) surrounding the chemoreceptor. The pH level, in turn, is determined by the level of hydrogen (H⁺) and bicarbonate (HCO₃⁻) ions as well as PCO₂ (see Appendix C for further discussion). The blood-brain barrier, the permeability properties of which influence the composition of cerebrospinal fluid (CSF) and brain ECF, prevents free movement of either H⁺ or HCO₃⁻ from blood to brain ECF, whereas CO₂ passes freely. The feedback loop for changes in PCO₂ can be summarized as follows:

The primary sensors for O₂ are not located in the CNS but rather in two peripheral chemoreceptors called the carotid body and aortic body chemoreceptors. The carotid chemoreceptors, which are quantitatively much more important than the aortic chemoreceptors, are located just beyond the bifurcation of each common carotid artery into the internal and external carotid branches. The aortic chemoreceptor is found between the pulmonary artery and the aortic arch. These chemoreceptors are sensitive to changes in PO₂, with hypoxia stimulating chemoreceptor discharge. In adults, the peripheral carotid body chemoreceptors also have a role in sensing PCO₂. Under normoxic conditions, the peripheral chemoreceptors are much less important than the central chemoreceptors for this purpose. However, arterial hypoxemia increases the sensitivity of the peripheral PCO₂ receptors, so if hypoxemia and hypercarbia are both present, the carotid body chemoreceptor will be maximally stimulated to increase ventilation. Peripheral chemoreceptor discharge is transmitted back to the CNS by cranial nerves: the glossopharyngeal nerve in the case of the carotid bodies and the vagus nerve for the aortic bodies. The information ultimately is transmitted to the medullary respiratory center so that its output is augmented.

The major sensors for PO₂ are the peripheral (carotid and aortic body) chemoreceptors.

Input from Other Receptors

In addition to chemoreceptor effects, input that originates from receptors in the lung (including the airways) and is carried via the vagus nerve to the CNS must be considered. Stretch receptors located within the smooth muscle of airway walls respond to changes in lung inflation. As the lung is inflated, receptor discharge increases. In animals, this stretch receptor reflex (the Hering-Breuer reflex) is responsible for apnea that occurs as a result of lung inflation. In contrast, conscious human adults do not readily demonstrate the Hering-Breuer reflex, and the role of the stretch receptors in ventilatory control is not entirely clear. Presumably, stretch receptors contribute to switching off inspiration and initiating expiration after a critical level of inspiratory inflation has been reached.

Irritant receptors located superficially along the lining of airways may initiate tachypnea, usually in response to some noxious stimulus such as a chemical or irritating dust. Juxtacapillary (or J) receptors are found within the pulmonary interstitium, adjacent to capillaries. One of their effects is to cause tachypnea, and they may be responsible for the respiratory stimulation caused by inflammatory processes or accumulation of fluid within the pulmonary interstitium.

Receptors in the chest wall, particularly in the intercostal muscles, appear to play a role in fine-tuning ventilation. The muscle spindles are part of a reflex arc that adjusts the output of respiratory muscles if the desired degree of muscular work has not been achieved. When a mismatch occurs between the output from the CNS controller and the amount of “stretch” sensed by these receptors, feedback from the receptors is involved in causing dyspnea. For example, for the patient with severe emphysema and lung hyperinflation, the increased output from the brain is not matched by an “appropriate” change in lung inflation. That is, the output does not match the result, so feedback is transmitted through the stretch receptors in the chest wall to the brain, and the patient experiences dyspnea. The precise mechanisms of these pathways are incompletely understood.

Ventilatory Response to Hypercapnia and Hypoxia

Two of the stimuli for ventilation that have been best studied are well-defined chemical stimuli: hypercapnia and hypoxia. Hypercapnia is sensed primarily but not exclusively by the central chemoreceptor, and the stimulus appears to be the pH level of brain ECF. In contrast, hypoxia stimulates ventilation by acting on peripheral chemoreceptors, carotid much more than aortic.

When arterial PO₂ is held constant, ventilation increases by approximately 3 L/min for each millimeter of mercury rise in arterial PCO₂ in adults. This relatively linear response, the magnitude of which varies considerably among individuals, is shown in Figure 17-2, which also shows that the response to increments in PCO₂ also depends on PO₂. At a lower PO₂, the response to hypercapnia is heightened.

Figure 17-2 Ventilatory response to progressive elevation of PCO₂ in normal individual. A, Solid line shows response when simultaneous PO₂ is high (hyperoxic conditions). B, Dashed line shows heightened response when simultaneous PO₂ is low (hypoxic conditions).

With chronic hypercapnia, the ventilatory response to further increases in PCO₂ is diminished. The reason for the blunted CO₂ responsiveness is relatively straightforward. When CO₂ retention persists for days, the kidneys compensate for the more acidic pH by excreting less bicarbonate, and the levels of bicarbonate rise in both plasma and brain ECF. The elevated bicarbonate level can buffer any acute changes in PCO₂ more successfully, so that the brain ECF pH value changes less for any given increment in PCO₂.

Ventilatory responsiveness to CO₂ is blunted in patients with chronic hypercapnia.

With hypoxemia, the same linear relationship does not exist between alterations in partial pressure and ventilation. Rather, the ventilatory response is relatively small until PO₂ falls to approximately 60 mm Hg, below which the rise in ventilation is much more dramatic (Fig. 17-3). The curvilinear relationship between PO₂ and ventilation can be made linear if ventilation is plotted against O₂ saturation instead of partial pressure (Fig. 17-4). However, despite the linear relationship between ventilation and O₂ saturation, it is the partial pressure of O₂, not the content or saturation, that is sensed by the chemoreceptor.

Figure 17-3 Ventilatory response to progressively decreasing PO₂ with PCO₂ kept constant in a normal individual. Ventilation does not rise significantly until PO₂ falls to approximately 60 mm Hg.

Figure 17-4 Ventilatory response to hypoxia, plotted using O₂ saturation rather than PO₂. Relationship between ventilation and O₂ saturation during progressive hypoxia is linear. A, Solid line shows response when measured at normal PCO₂. B, Dashed line shows augmented response at elevated PCO₂.

PCO₂ also has an effect on a patient’s response to hypoxia. The sensitivity to hypoxia is increased as PCO₂ is raised and is decreased as PCO₂ is lowered (see Fig. 17-4). This feature is important to consider when testing for responsiveness to hypoxia. As the patient hyperventilates in response to a low PO₂, PCO₂ drops, and ventilation is stimulated less than it would be if PCO₂ were unchanged. Therefore, PCO₂ should be kept constant so that the condition for testing actually is “isocapnic” hypoxia.

When the clinician suspects a disorder of ventilatory control, quantitation of the ventilatory response to hypercapnia or hypoxia can be performed. However, the responses to these stimuli vary widely even in seemingly normal individuals. This fact must be taken into account in the interpretation of ventilatory response data.

Ventilatory Response to Other Stimuli

One of the most important times for a rapid and appropriate increase in ventilation is in response to a change in metabolic requirements. For example, with the metabolic needs of exercise, a normal individual can increase ventilation from a resting value of 5 L/min to 60 L/min or more, without any demonstrable change in arterial blood gas values. According to one popular theory, the initial rapid increase in ventilation at the onset of exercise is due to a neural stimulus, although the origin is not clear. After the initial rapid augmentation in ventilation, there occurs a later and slower rise that probably is due to a bloodborne chemical stimulus. However, many questions about the remarkably appropriate way ventilation is capable of responding to the demands of exercise remain unanswered.

Another important ventilatory response occurs to alterations in acid-base status. With excess metabolic acid production (i.e., metabolic acidosis), ventilation increases as pH is lowered, and elimination of additional CO₂ aids in returning the pH toward normal. The peripheral chemoreceptors appear to be primarily responsible for sensing acute metabolic acidosis and stimulating the increase in ventilation, but how much the central chemoreceptors modify or contribute to this response is not entirely settled.

Respiratory Muscles

The purpose of signals emanating from the respiratory generator is to initiate inspiratory muscle activity. Although the primary inspiratory muscle is the diaphragm, other muscle groups contribute to optimal movement of the chest wall under a variety of conditions and needs. Notable among these other inspiratory muscle groups are the scalene and parasternal intercostal muscles, which display inspiratory activity even during normal quiet breathing. The so-called accessory muscles of inspiration (e.g., sternocleidomastoid and trapezius muscles) are not normally used during quiet inspiration but can be recruited when necessary, either when diaphragm function is impaired or when ventilation is significantly increased. Another set of intercostal muscles, the external intercostal muscles, are also inspiratory muscles, but their overall importance during inspiration is less clear. Finally, additional muscles coordinate upper airway activity during inspiration. Proper functioning of these muscles maintains patency of the upper airway, whereas dysfunction may be important in the pathogenesis of certain clinical disorders associated with upper airway obstruction, such as obstructive sleep apnea (see Chapter 18).

The diaphragm is the major muscle of inspiration. The less important inspiratory and accessory muscles may increase their role in disease states.

During inspiration, the diaphragm contracts and its muscle fibers shorten. To understand the effect of this contraction, consider the configuration of the diaphragm within the chest. At its lateral aspect, the diaphragm is adjacent to the inner part of the lower rib cage. This portion of the chest wall and the diaphragm is known as the zone of apposition (Fig. 17-5). In this region, the muscle fibers of the diaphragm are oriented vertically. When the diaphragm contracts, shortening of these vertically oriented fibers diminishes the zone of apposition and causes the more medial dome of the diaphragm to descend. At the same time, by pushing abdominal contents downward, diaphragmatic contraction increases not only intraabdominal pressure but also the lateral pressure on the lower rib cage transmitted through the apposed diaphragm. The effect of diaphragmatic contraction is thus to lift the lower ribs and expand the lower chest wall at the same time the abdominal wall moves outward. The external intercostal muscles, located between the ribs, also contract during inspiration, contributing as well to the lower rib cage being lifted and rotated outward.