Control of Ventilation

Reading assignment; West: Chapter 8

Overview

The primary function of the respiratory system is to take up oxygen and to remove carbon dioxide in order to maintain normal levels of arterial PO2 and PCO2. To accomplish this task there must be a mechanism for periodically inflating and deflating the lung. This control system must satisfy the following requirements:

1. It must be automatic. Maintenance of CO2 and O2 levels should not depend on levels of consciousness or alertness.
2. It must be adaptable to the needs of the organism. There must be mechanisms to compensate for changes in oxygen uptake or CO2 production. For example, during exercise there is a large increase in oxygen uptake and CO2 production which must be compensated for by increasing the rate of ventilation.
3. It must be subject to voluntary control. There must mechanisms to voluntarily override the respiratory control mechanisms at least for brief periods of time. Examples: breath holding diving; voluntary hyperventilation.

Organization of respiratory control

Central controller

Early studies of the neural control of breathing involved the section and ablation of various brainstem structures. From these studies emerged the classical description of the neural control of breathing that required centers in the medulla for the rhythmic generation of ventilatory drive plus additional areas in the pons (traditionally known as the pneumotaxic and apneustic centers) that modulated and regulated the basic rhythm (Figure 2).

Figure 2. The effects of transactions of different levels of the brainstem on the ventilatory pattern of anesthetized animals. If brain stem is sectioned at transection labeled C, breathing is maintained (although it is somewhat irregular). If the brainstem is transected at transection labeled D, breathing stops. If brain stem is sectioned at transection labeled B and the vagi have also been transected, a breathing pattern called apneusis results. Apneustic breathing consists of prolonged periods of inspiration interrupted by occasional expiration. If brain stem is sectioned at transaction labeled A, the breathing pattern is essentially normal.

• Primary centers responsible for the generation of respiratory rhythm are located in the medulla. Sectioning the brainstem below the medulla abolishes all respiratory activity. Sectioning above this region does not.
• Within the medulla, there are two bilateral aggregations of neurons having respiratory related activity (Figure 3).
• The dorsal respiratory group (DRG) neurons are primarily inspiratory (fire on inspiration) and are located in the nucleus tractus solitarius (NTS). These neurons project contralaterally to the phrenic and intercostal motor neurons in the spinal cord and provide the primary stimulus for respiration.
• The ventral respiratory group (VRG) is a long column of respiratory neurons, some of which are inspiratory (fire on inspiration) and some of which are expiratory (fire on expiration). It contains the nucleus ambiguus, which contains primarily inspiratory neurons that project to the larynx, pharynx and tongue. Stimulation of these neurons causes dilation of the upper airways which minimizes airway resistance during inspiration.
• An area of the ventrolateral medulla, the pre-Botzinger complex is hypothesized to be a critical site for mammalian rhythmogenesis.

Afferent inputs including chemoreceptors and pulmonary stretch receptors

The brainstem controller receives information from a variety of sources. Some of these involve the relatively straightforward chemoreceptor signals that provide closed-loop information on the gap exchange functions of the lung. These signals arise mainly from the central and peripheral chemoreceptors that mediate the response to hypoxia, hypercapnia, and acidemia. Because the stimuli can be can be relatively unambiguously defined, these reflexes have been extensively studied. However, there are obviously many other inputs that may, at any given time, be important in determining ventilatory drive.

The states of cortical arousal and of emotion play important roles in the level of ventilation and the response to other stimuli. This has been extensively studied in terms of the sleep state. The control of ventilation during exercise and changes in metabolic rate involve afferent information from body temperature and a wide variety of joint, muscle and nociceptive receptors. It is not known if these receptors have specific connections to ventilatory control centers or are less specifically coupled through the reticular activating network in the surrounding brainstem.

There are also important receptors in the lung and the upper respiratory tract that provide afferent information to the respiratory centers. This information is used in normal ventilation (e.g. vagal feedback of lung volume from pulmonary stretch receptors) as well as to initiate maneuvers such as sneezing and coughing that need to override the gas exchanging role of the ventilatory system.

Central chemoreceptors

There are several regions on the dorsal surface of the brainstem that cause a reflex increase in phrenic nerve activity when the local CSF is acidified. When these areas were initially identified, it seemed that there were only a few very discrete regions of chemosensitivity. However, more recent studies have identified multiple sites throughout the brainstem that contain neurons which are sensitive to changes in pH.

While the central chemoreceptors respond to either local increases in CO2 or decreases in pH, it is thought that the primary signal is the change in intracellular H+ ions. However, since the chemoreceptors are located on the brain side of the blood-brain barrier and H+ ions do not readily cross the blood-brain barrier, the central chemoreceptors are much more sensitive to increases in P_aCO2 than to decreases in blood pH.

The central chemoreceptors are not sensitive to blood PO2.

Figure 4. Environment of the central chemoreceptors. They are bathed in brain extracellular fluid (ECF) through which CO2 easily diffuses from blood vessels to cerebrospinal fluid (CSF). The CO2 reduces the CSF pH, thus stimulating the chemoreceptor: H+ and HCO3- ions cannot easily cross the blood-brain barrier. From JB West, Respiratory Physiology-The Essentials, 7th ed.

Peripheral chemoreceptors

The peripheral chemoreceptors include the carotid bodies and the aortic bodies. The carotid bodies are much more important than the aortic bodies in humans. The peripheral chemoreceptors are sensitive to hypoxia and hypercapnia/acidosis.

The site of chemoreception in the carotid body has been localized to the type I glomus cells; the type II cells are felt to play more of a supporting role similar to that of glial cells. The hypoxic response causes a sharp increase in firing rate of the carotid sinus nerve when the P_aO2 is lowered below 60 mmHg (Figure 5).

Figure 5. A. Diagram of a carotid body which contains type I and type II cells with many capillaries (Cap). Impulses travel to the central nervous system (CNS) through the carotid sinus nerve. B shows the nonlinear response to arterial PO2. Note that the maximum response occurs below a PO2 of 50 mm Hg. From JB West, Respiratory Physiology-The Essentials, 7th ed.

Signal transduction involves the depolarization of the type I cells. The coupling of the change in O2 to the change in membrane potential appears to occur through a potassium channel that is normally open at resting membrane potential (Figure 5). However, how the decrease in oxygen closes the channel is still an area of active research.

After the transduction in the type I cells, the signal needs to be coupled to the carotid sinus nerve endings. Rather than there being a single neurotransmitter, there appears to be multiple inhibitory and excitatory neurochemicals that function both as classical neurotransmitters and also as neuromodulators. Dopamine is abundant in type I cells but it seems to be an inhibitory neurotransmitter. Currently there is good evidence that ATP functions as the primary excitatory neurotransmitter, perhaps co-released with Ach. There is also the opportunity for efferent modulation of CB function through sympathetic and parasympathetic innervation.

Figure 6. Oxygen sensing by carotid body glomus cells. These cells are presynaptic-like elements in close proximity with capillaries that form synapses with afferent sensory fibers of the sinus nerve. Reduction of blood O2 tension causes closure of K+ channels and cell depolarization (ΔVm). The change in membrane potential opens voltage-gated Ca2+ channels, elevates cytosolic [Ca2+], and triggers transmitter release. The nature of the O2 sensor and the mechanism by which changes of O2 tension regulate K+ channel activity are still unknown (question marks).

Pulmonary mechanoreceptors

Figure 7. Neural afferents from all levels of the respiratory tract initiate various respiratory reflexes.

While the chemoreceptors provide primary feedback signals for controlling the magnitude of ventilation, reflexes from all along the respiratory tract provide information to the respiratory centers that will modify or sometimes even block this drive (Figure 7).

For example, the diving reflex can be elicited by water (particularly cold) on the face or in the nose, and cause apnea and laryngeal closure. While it is stronger in diving animals, it can also be found in humans. Many of the reflexes of the airway are involved in protection, either through trying to clear the airway of foreign material through sneezing or coughing, or in preventing aspiration by closing the larynx during the swallowing of emesis.

Pharyngeal reflexes are also important in maintaining a patent airway. During inspiration the pressure in the aiway is negative and since there are no intrinsic structures to hold the pharyngeal airway open (like the tracheal cartilages), muscle tone must provide the counter forces to keep the airway open. There are receptors in the pharynx that sense this negative pressure and signal the need for increased drive to the upper airway muscles during inspiration. In obstructive sleep apnea, this reflex may not be sufficient to overcome the forces that collapse the airway during inspiration.

Reflexes in the lower airway (tracheal bronchial tree) are also involved in both shaping the ventilatory pattern and protecting the airway. Rapidly adapting pulmonary stretch receptors are so named since during constant stimulation they initially fire very rapidly but then soon decrease their firing rate (Figure 8).

Figure 8.

These receptors are located between airway epithelial cells and are found in abundance throughout the carina and subsequent bronchial bifurcations. This is where contaminates in the inspired air (particles) are most likely to impact because of their mass. They are stimulated by irritant gases, histamine and rapid or extreme lung inflation (Figure 9). They mediate reflex cough, bronchoconstriction and hyperpnea.

Figure 9. Rapidly adapting receptors are stimulated by irritants such as smoke and dust.

Another type of lung receptor is the slowly adapting pulmonary stretch receptor (or PSR) which can be distinguished from the rapidly adapting airway receptor by its response to lung inflation (Figure 10).

Figure 10. Slowly adapting receptors fire at a constant rate in response to lung inflation.

These receptors are located in airway smooth muscle and carry impulses in the vagus nerve via large myelinated fibers. They are activated by high lung volume or bronchoconstriction and mediate the Hering-Breuer reflex (early termination of inspiration).

An additional lung receptor is the so-called J receptor whose impulses are carried in small unmyelinated C fibers of the vagus nerve. They have been called J receptors because the nerve endings are often found near (‘juxta’) the alveolus. They respond to mechanical deformation (e.g. pulmonary edema). Activation of these receptors causes rapid, shallow breathing and dyspnea.

INTEGRATED VENTILATORY RESPONSES

The ventilatory response to CO2

CO2 is the most important factor in the control of ventilation under normal circumstances. The PaCO2 is held within 3 mm Hg of 40 mm Hg during the course of daily activity with periods of rest and exercise. During sleep, it may vary a little more. Increasing PaCO2 acts via a negative feedback loop to increase alveolar ventilation. Although both the central and peripheral chemoreceptors respond to hypercapnia, frequently the reflex is studied in hyperoxia, which in humans, effectively removes the peripheral component. While the carotid body response under normal circumstances provides only 20-30% of the total hypercapnic response, the response is faster with a time constant of 10-30 seconds. The central response is slower with a time constant in the range of 60-150 seconds. This slow central response requires that 5-6 minutes of hypercapnia be maintained in order to reach steady-state ventilation.

Steady-state ventilation has an apparently linear relationship to increasing PaCO2 (Figure 11 ). The hypercapnic response is usually described by a slope (lmin^-1mmHg^-1) and an intercept. Normal values for the hypercapnic response slope range between 1-2 lmin^-1mmHg^-1. The intercept may be given as the intersection of the response line with either the CO2 or the ventilation axis.

Figure 11. Ventilatory response to CO2. Each curve of total ventilation against alveolar PO2 values of 110 mm Hg and 169 mm Hg, though some investigators have found that the slope of the line is slightly less at the higher PO2.

Reducing PAO2 shifts the CO2 response curve to the left and increases its slope.

There are a number of other factors that can influence the response to CO2 as illustrated in Figure 12. For example, opiates such as morphine are essential drugs for the relief of severe pain, but they have profound effects on ventilatory control. Characteristically ventilation is markedly reduced and there is resting hypercapnia. Large doses can cause apnea with a rapidly rising CO2 and falling O2. The ventilatory response to hypercapnia is shifted to the right (Figure 12) but the slope is often not greatly altered until the patient falls asleep or high doses are given.

Figure 12. The effects of sleep, narcotics, chronic pulmonary obstructive pulmonary disease, deep anesthesia, and metabolic acidosis on the ventilatory response to carbon dioxide. From MG Levitzky, Pulmonary Physiology, 5th ed.

Hypoxic Ventilatory response

The ventilatory response to hypoxia has been subjected to extensive physiological study, particularly with regard to acclimatization to high altitude. Since the discovery of peripheral chemoreceptors, much work has focused on the ventilatory stimulating effects of hypoxia. In humans, this response is almost solely due to the carotid body. There is very little ventilatory response until the arterial oxygen is lowered below 60 mm Hg. and then there is a sharp increase just as in the firing rate of the carotid sinus nerve (see Figure 5). Adding inspired CO2 to create a hypercapnic situation greatly augments the hypoxic response (Figure 13). Hypoxia and hypercapnia interact at the level of the carotid body and studies in patients who have had their carotid bodies removed (an old and unproved treatment for dyspnea) showed no interaction between hypoxia and hypercapnia. The combination of hypoxia and hypercapnia (asphyxiation) is an extremely powerful stimulus to ventilation.

Figure 13. The ventilatory responses to hypoxia at three different levels of arterial PCO2. From MG Levitzky, Pulmonary Physiology, 5th ed.

• Abnormal breathing patterns
  • Cheyne-Stokes
    • Following an apneic period VT and f increase progressively then decrease again until another period of apnea is seen
    • seen in patients with injuries to the head or low cardiac output and reduced brain flow. Also occasionally seen in normal individuals at high altitudes.
  • Apneustic breathing
    • Sustained periods of inspiration followed by brief periods of expiration
    • Can be caused by CNS injury
    • Sleep apnea – upper airway blocked, similar to snoring, but more extreme
    • In central sleep apnea there is a decrease in ventilatory drive leading to apnea