Location and Response

The central chemoreceptors are chemosensitive areas located on the medulla of the brain. These chemoreceptors in the medulla should not be confused with the medullary respiratory center, because they are distinctly separate entities. The chemoreceptors are bathed in cerebrospinal fluid (CSF) and respond directly to the pH of the cerebrospinal fluid. When the hydrogen ion concentration of the CSF increases (i.e., pH decreases), an increase in ventilation is triggered. Conversely, when the pH of the CSF increases, the ventilatory drive and the volume of ventilation are diminished. The central chemoreceptors do not respond to oxygen levels in the blood.

Blood-Brain Barrier

The CSF is separated from the blood by the blood-brain barrier, which is readily permeable to gases but relatively impermeable to ions. Gases equilibrate quickly across the blood-brain barrier. Some ions, such as bicarbonate, may tend to equilibrate across the barrier, but the exchange process is active transport rather than simple diffusion. The active transport of ions across the blood-brain barrier may take a considerable time (i.e., hours to days)⁸¹ compared with the immediate diffusion of gases.

Thus, when the PaCO₂ increases, PCO₂ in the CSF immediately follows suit. This, in turn, lowers the pH of the CSF, and the ventilatory drive is augmented within minutes. In metabolic acidosis, however, the bicarbonate ion is transported slowly out of the CSF. Therefore, it takes longer for the pH of the CSF to decrease, and consequently the ventilatory response is delayed.

Cheyne-Stokes Ventilation

It is noteworthy that even with respiratory (i.e., PCO₂) gas changes, there is some delay from the time when the alveolar PCO₂ changes until this change is reflected in the CSF. This time delay explains why the ventilatory response to increased or decreased alveolar PCO₂, although highly sensitive, is not instantaneous. Furthermore, if circulation is impaired, such as in congestive heart failure, this delay may be exaggerated because it takes longer for blood from the lungs to reach the medulla. In theory, this circulatory delay may explain the Cheyne- Stokes breathing that is sometimes observed in congestive heart failure.

Cheyne-Stokes breathing is a recurrent pattern of ventilation characterized by a progressive rise and fall of tidal volume (Fig. 12-2). A period of apnea may sometimes occur between cycles. The related alveolar and central chemoreceptor PCO₂ levels at different points in the breathing cycle are also shown in Figure 12-2.

Location

The second group of chemosensitive cells (chemoreceptors) that affects ventilation is located adjacent to the walls of certain arterial blood vessels. These peripheral chemoreceptors are located in two distinct anatomic areas: the carotid and aortic bodies.

The carotid bodies are a group of cells located near the bifurcation of the common carotid artery into the internal and external carotid arteries. They appear as small, pink nodules, approximately 3 to 5 mm in diameter.⁸¹ The aortic bodies are located within the arch of the aorta.

The two sets of cells, which are referred to collectively as the peripheral chemoreceptors, serve to chemically monitor the blood passing by them. To perform this function, the peripheral chemoreceptors receive a relatively large blood flow in proportion to their size.

Responsiveness

Unlike the central chemoreceptors, the peripheral chemoreceptors respond to several different blood gas stimuli: the PaO₂, arterial pH, and PaCO₂. In addition, when blood flow past the peripheral chemoreceptors is diminished (e.g., in shock), an increase in ventilation is also stimulated. The peripheral chemoreceptors generally do not respond to anemia (e.g., methemoglobinemia, HbCO poisoning), although there is some response when anemia is severe. Interestingly, the peripheral chemoreceptors stimulate severe hyperpnea (increased tidal volume) in cyanide poisoning.⁸¹

PaCO₂/pH

Although both the peripheral and central chemoreceptors respond to increased PaCO₂ and decreased pH, they are not equally sensitive to these stimuli. Specifically, a relatively large increase in PaCO₂ or a decrease in pH (e.g., PaCO₂ increase = 10 mm Hg; pH decrease = 0.1)⁸¹ is necessary before a notable increase in ventilation will be triggered via the peripheral chemoreceptors. Conversely, the central chemoreceptors respond to very slight changes in PaCO₂. In a normal young man, minute ventilation increases approximately 2.5 L with only a 1-mm Hg increase in PaCO₂.⁸¹

PaO₂

The response of the peripheral chemoreceptors to a low PaO₂ sets them apart from the central chemoreceptors and is their most important mechanism clinically. Even in normal humans, some, albeit few, impulses are sent to the brain from the peripheral chemoreceptors stimulating ventilation. PaCO₂ and the central chemoreceptors are the primary mechanisms of ventilatory control during normal ventilation.

Regulation of ventilation in pulmonary disease is often in marked contrast. Here, the peripheral chemoreceptors often play the dominant role in determining the ventilatory pattern. The number of peripheral chemoreceptor impulses sent to the brain to stimulate ventilation in hypoxemia may increase greatly. Initially, ventilatory impulses increase only slightly as PaO₂ falls slightly below the normal range. When PaO₂ falls below 60 mm Hg, however, there is a dramatic increase in impulse production and ventilation.

Not only do the peripheral chemoreceptors greatly stimulate ventilation when PaO₂ falls below this critical point; they also stimulate the cardiovascular system. Clinically, this is manifested by a rise in heart rate and arterial blood pressure. Restoration of PaO₂ to normal, however, allows ventilation, heart rate, and blood pressure to return to normal levels.

Normal Ventilation

The regulation of ventilation in normal individuals is primarily under the control of the central chemoreceptors; however, as previously mentioned, the peripheral chemoreceptors send weak messages to the brain to ventilate and have some, albeit small, influence on the ventilatory pattern. Thus, the ventilatory pattern is the net result of the integration of the two sets of chemoreceptors.

Acute Hypoxemia

In the presence of disease, the peripheral chemoreceptors may take the dominant role in the regulation of ventilation. For example, in acute, severe hypoxemia, the peripheral chemoreceptors send a powerful message to the brain to increase ventilation and generally will override the central chemoreceptors. Subsequently, the increased ventilation that accompanies severe, acute hypoxemia lowers PaCO₂. The decreased PaCO₂, in turn, has the effect of making the CSF alkalotic and depressing ventilation via the central chemoreceptors.

Thus, in acute hypoxemia, two conflicting messages are sent to the brain. The severe hypoxemia requires an increase in ventilation via the peripheral chemoreceptors, whereas the low PaCO₂ depresses the central chemoreceptors. Because the number of impulses resulting from severe hypoxemia is large and the decrease in impulses resulting from the falling PaCO₂ is small, the individual will display a net increase in ventilation. It is important to recognize, however, that the central chemoreceptors tend slightly to blunt the hyperventilation.

Chronic Hypoxemia

In chronic hypoxemia, PaCO₂ also remains low. After a few hours, however, the pH of the CSF, made alkalotic by the hypocarbia, begins to return to normal as bicarbonate ions are actively transported out of the blood-brain barrier. When the pH of the CSF returns to normal, it no longer depresses ventilation via the central chemoreceptors. At this point, the individual actually begins to hyperventilate to a greater degree. It is, in fact, well known that the ventilatory response to chronic hypoxemia is greater than the ventilatory response to acute hypoxemia because of this mechanism.⁸¹ Again, the ventilatory pattern at any point in time depends on the interaction of the chemoreceptors.

Progressive Pulmonary Deterioration

Lung diseases, such as emphysema, chronic bronchitis, and chronic asthma, are often grouped into a single category called chronic obstructive lung disease (COLD), chronic obstructive pulmonary disease (COPD), or chronic airflow obstruction (CAO). A common denominator of these diseases is that they may lead to a progressive inability of the lungs to normally exchange gases and maintain ventilation.

Normal Lung Function

The effects of progressive pulmonary deterioration on the chemoreceptors and blood PaCO₂ and PaO₂ levels are shown in Table 12-1. Normal lung function is associated with normal blood gases and ventilation is primarily under the control of the central chemoreceptors.

Mild Disease

The initial blood gas abnormality associated with mild pulmonary disease is mild hypoxemia with a normal PaCO₂ (see Table 12-1). In this early stage, the increase in peripheral chemoreceptor stimulation is so minute that it is not clinically detectable. The central chemoreceptors maintain primary control over ventilation.

Moderate Disease

As deterioration in external respiration continues, PaO₂ continues to decline. At a PaO₂ level of approximately 60 mm Hg (although there may be considerable individual variation with regard to the specific PaO₂ when this occurs), a dramatic increase in peripheral chemoreceptor stimulation is seen, and the peripheral chemoreceptors assume primary control of ventilation. The strong peripheral chemoreceptor drive usually results in an increase in alveolar ventilation and a fall in the PaCO₂ (see Table 12-1).

It is important to note that, during this phase, the cardiovascular system is also required to increase the heart rate and to elevate the blood pressure. From a teleologic perspective, because O₂ levels are falling to a critical point on the oxyhemoglobin curve, the cardiovascular system appears to be trying to ensure sufficient tissue O₂ delivery.

Severe Disease

If external respiration continues to deteriorate, CO₂ excretion is ultimately impaired and PaCO₂ levels begin to increase. Furthermore, PaO₂ levels continue to fall (see Table 12-1). Indeed, the classic definition of acute respiratory failure is a PaCO₂ greater than 50 mm Hg and/or a PaO₂ less than 50 mm Hg.

The same pattern of progressive pulmonary deterioration can also occur over a short time (days or hours) in acute pulmonary disease. This pattern may be observed in pneumonia, postoperative respiratory failure, or acute asthma. It is always important to identify patients with moderate impairment (i.e., moderate disease as described in Table 12-1), because further deterioration leads to hypercarbia. The classic example of this is the patient in status asthmaticus (sustained unresponsive asthma) whose condition deteriorates progressively over a period of days, leading ultimately to exhaustion and to the abrupt onset of respiratory acidemia.

In patients with severe chronic lung disease, administration of oxygen may lead to progressive hypercapnia and occasionally even to apnea. For years, it was believed that this occurred because these patients were breathing exclusively in response to the so-called hypoxic drive of the peripheral chemoreceptors. It was assumed that the central chemoreceptors had become dulled because of the chronic hypercarbia; it followed, then, that oxygen therapy increased the PaO₂ and knocked out the drive to breathe.

Other studies have shown that the worsening hypercarbia associated with oxygen therapy in these patients is more likely a result of ventilation-perfusion alterations than a result of a decrease in ventilatory drive.⁴⁶³ Furthermore, the Haldane effect (release of CO₂ from Hb into the blood in the presence of increased oxygen) may be responsible for some of the ensuing hypercarbia.⁴⁶⁴ The precise mechanism responsible for this hypoventilation remains a controversial issue and multiple factors may be influencing ventilation simultaneously. Regardless of the exact mechanism, worsening hypercarbia must be recognized as a possible consequence of oxygen therapy in chronic lung disease.