Control of Respiration

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. This 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, limbic system including the amygdalae, 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 Pa co ₂ 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 Pa o ₂ , Pa co ₂ , and pH of arterial blood. They feed information back to the integrator nuclei in the medulla through the vagus nerves, and by the carotid sinus nerves that 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 Carbon Dioxide

Ventilation is also regulated by Pa co ₂ , Pa o ₂ , and pH in arterial blood. Pa co ₂ is the most important of these regulators. Both the rate and depth of breathing are controlled to maintain Pa co ₂ close to 40 mm Hg. In a normal awake individual, there is a linear rise in ventilation as Pa co ₂ reaches and exceeds 40 mm Hg ( Fig. 25.1 ). The ventilatory drive or response to changes in Pa co ₂ can be reduced by hyperventilation and by drugs that depress the respiratory center and decrease the ventilatory response to both CO ₂ and O ₂ . These drugs include opiates, benzodiazepines, barbiturates, and anesthetic agents. 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 Pa co ₂ is reduced if the work of breathing is increased, which can occur in individuals with chronic obstructive pulmonary disease (COPD). 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.

Changes in Pa co ₂ 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 Pa co ₂ within the normal range. In the presence of a normal Pa o ₂ , ventilation increases by approximately 3 L/minute for each 1 mm Hg rise in Pa co ₂ . The response to an increase in Pa co ₂ is further increased when the Pa o ₂ is low ( Fig. 25.2 A ). With a low Pa o ₂ , ventilation is greater for any given Pa co ₂ , and the increase in ventilation for a given increment in Pa co ₂ is enhanced. The slope of the minute ventilation response as a function of the inspired CO ₂ is termed the ventilatory response to CO ₂ and is a test of CO ₂ sensitivity. It is important to recognize that this relationship is amplified by low O ₂ (see Fig. 25.2 B ). The responsiveness to low O ₂ is enhanced because different mechanisms are responsible for sensing Pa o ₂ and Pa co ₂ in the peripheral chemoreceptors. Thus the presence of both hypercapnia-elevated CO ₂ and hypoxemia-low O ₂ (often called asphyxia when both changes are present) has an additive effect on chemoreceptor output and on the resulting ventilatory stimulation.

Control of Ventilation: The Details