VENTILATORY CONTROL: AN OVERVIEW

There are four major sites of ventilatory control: (1) the respiratory control center, (2) central chemoreceptors, (3) peripheral chemoreceptors, and (4) pulmonary mechanoreceptors/sensory nerves. The respiratory control center is located in the medulla oblongata of the brainstem and is composed of multiple nuclei that generate and modify the basic ventilatory rhythm. The center consists of two main parts: (1) a ventilatory pattern generator, which sets the rhythmic pattern, and (2) an integrator, which controls generation of the pattern, processes input from higher brain centers and chemoreceptors, and controls the rate and amplitude of the ventilatory pattern. Input to the integrator arises from higher brain centers, including the cerebral cortex, hypothalamus, amygdala, limbic system, and cerebellum.

Central chemoreceptors are located in the central nervous system just below the ventrolateral surface of the medulla. These central chemoreceptors detect changes in the PCO₂ and pH of interstitial fluid in the brainstem, and they modulate ventilation. Peripheral chemoreceptors are located on specialized cells in the aortic arch (aortic bodies) and at the bifurcation of the internal and external carotid arteries (carotid bodies) in the neck. These peripheral chemoreceptors sense the PO₂, PCO₂, and pH of arterial blood, and they feed information back to the integrator nuclei in the medulla through the vagus nerves and carotid sinus nerves, which are branches of the glossopharyngeal nerves. Pulmonary mechanoreceptors and sensory nerve stimulation, in response to lung inflation or to stimulation by irritants or release of local mediators in the airways, modify the ventilatory pattern.

The collective output of the respiratory control center to motor neurons located in the anterior horn of the spinal column controls the muscles of respiration, and this output determines the automatic rhythmic pattern of respiration. Motor neurons located in the cervical region of the spinal column control the activity of the diaphragm through the phrenic nerves, whereas other motor neurons located in the thoracic region of the spine control the intercostal muscles and the accessory muscles of respiration.

In contrast to automatic respiration, voluntary respiration bypasses the respiratory control center in the medulla. The neural activity controlling voluntary respiration originates in the motor cortex, and signaling passes directly to motor neurons in the spine through the corticospinal tracts. The motor neurons to the respiratory muscles act as the final site of integration of the voluntary (corticospinal tract) and automatic (ventrolateral tracts) control of ventilation. Voluntary control of these muscles competes with automatic influences at the level of the spinal motor neurons, and this competition can be demonstrated by breath holding. At the start of the breath hold, voluntary control dominates the spinal motor neurons. However, as the breath hold continues, the automatic ventilatory control eventually overpowers the voluntary effort and limits the duration of the breath hold. Motor neurons also innervate muscles of the upper airway. These neurons are located within the medulla near the respiratory control center. They innervate muscles in the upper airways through the cranial nerves. When activated, they dilate the pharynx and large airways at the initiation of inspiration.

RESPONSE TO CO₂

Ventilation is regulated by PCO₂, PO₂, and pH in arterial blood. Arterial PCO₂ is the most important of these regulators. Both the rate and depth of breathing are controlled to maintain PaCO₂ close to 40 mm Hg. In a normal awake individual, there is a linear rise in ventilation as arterial PCO₂ reaches and exceeds 40 mm Hg (Fig. 24-1). Changes in PaCO₂ are sensed by central and peripheral chemoreceptors, and they transmit this information to the medullary respiratory centers. The respiratory control center then regulates minute ventilation and thereby maintains arterial PCO₂ within the normal range. In the presence of a normal PAO₂, ventilation increases by about 3 L/min for each millimeter rise in PaCO₂. The response to an increase in PACO₂ is further increased in the presence of a low PaO₂ (Fig. 24-2). With a low Pao₂, ventilation is greater for any given PACO₂, and the increase in ventilation for a given increment in PACO₂ is enhanced (the slope is greater).

Figure 24-1 Relationship between PaCO₂ and alveolar ventilation in awake normal states, during sleep, after narcotic ingestion and deep anesthesia, and in the presence of metabolic acidosis. Both the slopes of the response (sensitivity) and the position of the response curves (threshold, the point at which the curve crosses the x axis) are changed, thus indicating differences in ventilatory responses and response thresholds.

Figure 24-2 The effects of hypoxia (A) and hypercapnia (B) on ventilation as the other respiratory gas partial pressure is varied. A, At a given PaCO₂, ventilation increases more and more as PaO₂ decreases. When PaCO₂ is allowed to decrease (the normal condition) during hypoxia, there is little stimulation of breathing until PO₂ falls below 60 mm Hg. The hypoxic response is mediated through the carotid body chemoreceptors. B, The sensitivity of the ventilatory response to CO₂ is enhanced by hypoxia.

The slope of the minute ventilation response as a function of the inspired CO₂ is termed the ventilatory response to CO₂ and is a test of CO₂ sensitivity. It is important to recognize that this relationship is amplified by low O₂ (Fig. 24-2, B). The enhanced responsiveness to low O₂ occurs because different mechanisms are responsible for sensing PO₂ and PCO₂ in the peripheral chemoreceptors. Thus, the presence of both hypercapnia and hypoxemia (often called asphyxia when both changes are present) has an additive effect on chemoreceptor output and on the resulting ventilatory stimulation.

The ventilatory drive or response to changes in PCO₂ can be reduced by hyperventilation and by drugs, such as morphine, barbiturates, and anesthetic agents, that depress the respiratory center and decrease the ventilatory response to both CO₂ and O₂ (Fig. 24-1). In these instances, the stimulus is inadequate to stimulate the motor neurons that innervate the muscles of respiration. It is also depressed during sleep.

In addition, the ventilatory response to changes in PCO₂ is reduced if the work of breathing is increased, which can occur in individuals with chronic obstructive pulmonary disease (COPD) (Fig. 24-1). This effect occurs primarily because the neural output of the respiratory center is less effective in promoting ventilation as a result of the mechanical limitation to ventilation.

CONTROL OF VENTILATION: THE DETAILS

The Respiratory Control Center

When the brain is transected experimentally between the medulla and the pons, periodic breathing is maintained, thus demonstrating that the inherent rhythmicity of breathing originates in the medulla. Although no single group of neurons in the medulla has been found to be the breathing “pacemaker,” two distinct nuclei within the medulla are involved in generation of the respiratory pattern (Fig. 24-3). One nucleus is the dorsal respiratory group (DRG), which is composed of cells in the nucleus tractus solitarius located in the dorsomedial region of the medulla. Cells in the DRG receive afferent input from the 9th and 10th cranial nerves, which originate from airways and the lung and are thought to constitute the initial intracranial processing station for this afferent input. The second group of medullary cells is the ventral respiratory group (VRG), located in the ventrolateral region of the medulla. The VRG is composed of three cell groups: the rostral nucleus retrofacialis, the caudal nucleus retroambiguus, and the nucleus paraambiguus. The VRG contains both inspiratory and expiratory neurons. The nucleus retrofacialis and the caudally located cells of the nucleus retroambiguus are active during exhalation, whereas the rostrally located cells of the nucleus retroambiguus are active during inspiration. The nucleus paraambiguus has inspiratory and expiratory neurons that travel in the vagus nerve to the laryngeal and pharyngeal muscles. Discharges from cells in these areas excite some cells and inhibit other cells.