The regulation of breathing

The role of the central nervous system

The respiratory cycle uses specific neurologic circuits and muscular groups ( Table 16.1 ):

• Stimulation of respiratory centers → efferent nerves → activation of motor neurons in cervical, thoracic, and lumbar spinal cord → innervation of diaphragm, intercostal muscle (m.), and abdominal m. (respectively) → inspiration (see Clinical Correlation Box 16.1 ).

  Clinical Correlation Box 16.1

  Efferents from cervical motor neurons C3–C5 form the phrenic nerves, which drive relaxed tidal breathing. The phrenic nerves provide the only motor supply the diaphragm, which upon contraction expands the volume of the thoracic cavity and draws air into the lungs. Damage to the phrenic nerve or its cervical roots, as with traumatic head and neck injury, may lead to diaphragmatic paralysis and mechanical ventilation dependence.

  Mnemonic: “C3, 4, 5, keeps the diaphragm alive!”

• Cessation of stimulation → inspiratory muscles relax → lung recoils because of elasticity of lungs → passive expiration.

• Activation of additional expiratory muscles (abdominal recti & internal intercostal m.) → active expiration.

Voluntary and involuntary impulses are transmitted through different pathways in the spinal cord ( Fig. 16.3 ):

• Voluntary nerve fibers are located within the dorsolateral corticospinal tracts.

• Involuntary nerve fibers are located within the medial portion of anterior horn.

There are three main respiratory control centers in the central nervous system (CNS): the medulla, the pons, and the cerebral cortex.

• 1.

  Medulla (reticular formation) ( Fig. 16.4 )

  • Dorsal respiratory group (DRG)

  • Maintains inspiratory rhythm during tidal breathing

  • Located in the nucleus tractus solitarii

  • Modulated by chemoreception (PCO ₂ , PO ₂ , pH), mechanoreception (lung stretch), and nociception.

  • Receives input from the vagus (CNX) and glossopharyngeal (CNIX) nerves (n.)

  • Produces a “ramp signal” to phrenic n. to regulate respiratory rate and tidal volume ( Fig. 16.5 ).

    

  • Ventral respiratory group (VRG)

  • Augments active respiration (i.e., during exercise)

  • Composed of:

    • Nucleus paraambiguus (active during inspiration)

    • Caudal nucleus retroambiguus (active during exhalation)

    • Rostral nucleus retrofacialis (active during exhalation)

    • Pre-Bötzinger complex (central rhythm generation)

  • Receives stimulation from the DRG

  • Increases DRG ramp signal and recruits expiratory m. of respiration (i.e., abdominal recti).

  

• 2.

  Pons (see Fig. 16.4 )

  • Pneumotaxic center

  • Coordinates speed of inhalation and exhalation.

  • Located in the upper pons (nucleus parabrachialis)

  • Inhibits DRG and thus lowers the threshold for ramp signal cessation

    • ↑ pneumotaxic signal → ↓ ramp signal duration →↓ duration of inspiration, ↓ tidal volume, ↑ respiratory rate (RR)

    • ↓ pneumotaxic signal → ↑ ramp signal duration → ↑ duration of inspiration, ↑ tidal volume, ↓ RR

  • Apneustic center

  • Coordinates speed of inhalation and exhalation

  • Located in the caudal pons adjacent to the DRG and VRG

  • Receives inhibitory input from the pneumotaxic center

  • Stimulates DRG and thus raises the threshold for ramp signal cessation

    • ↑ apneustic signal → ↑ ramp signal duration → ↑ duration of inspiration, ↑ tidal volume, ↓ RR

    • ↓ apneustic signal → ↓ ramp signal duration →↓ duration of inspiration, ↓ tidal volume, ↑ RR

• 3.

  Cerebral Cortex

  • Function: Voluntary hypo- or hyperventilation (see Genetics Box 16.1 , Pharmacology Box 16.1 , Fast Fact Box 16.1 , and Fast Fact Box 16.2 ).

GENETICS BOX 16.1

Congenital central hypoventilation syndrome is a rare disease that underscores the critical importance of involuntary control of breathing. Affected children hypo-ventilate (especially when sleeping), retain carbon dioxide, and do not reflexively increase ventilation in response to higher CO ₂ levels. This disease is caused by a mutation in the PHOX2B gene that encodes a protein important in the development of central nervous system (CNS) chemoreceptor areas. The mutation alters a single amino acid and results in this potentially life-threatening disease.

PHARMACOLOGY BOX 16.1

Central sleep apnea is a disease in which the involuntary respiratory drive is abnormal. It can be treated with acetazolamide, a medication that induces a mild metabolic acidosis (see Ch. 22 on acid base balance) and thereby stimulates respiration. Theophylline antagonizes phosphodiesterase, increasing concentrations of cyclic adenine monophosphate (cAMP) leading to catecholamine stimulation of various tissues including central respiratory centers.

The role of central chemoreceptors

Under normal conditions, central chemoreceptors just below the ventrolateral surface of the medulla supply the most important sensory inputs to the medullary respiratory centers. Instead of relaying input peripheral chemoreceptors, they detect chemical changes in their immediate environment and transmit this information to the respiratory centers in the medulla and pons.

The central chemoreceptors react to the arterial partial pressure of carbon dioxide (PaCO ₂ ). PaCO ₂ affects the central chemoreceptors indirectly by increasing the cerebrospinal fluid (CSF) H ⁺ concentration, which stimulates the central chemoreceptive neurons ( Fig. 16.6 ). PaCO ₂ and H ⁺ are related to one another by the blood buffer equation (see Ch. 22 ):

Given that the central chemoreceptors respond directly only to H ⁺ , one might conclude that low arterial pH (high H ⁺ concentration) would stimulate the chemoreceptors. However, this is not the case: cationic H+ ions cannot cross the blood-brain barrier. Instead, increasing PaCO ₂ drives dissolved CO ₂ across the blood-brain barrier, which increases the CO ₂ content of CSF. CO ₂ is then readily hydrated to carbonic acid, which then dissociates to produce bicarbonate and H ⁺ . These H ⁺ ions then bind the central chemoreceptors, which stimulates an increase in respiratory drive ( Fig. 16.7 ).

In other words:

↓ ventilation → ↑ PaCO ₂ → ↓ CSF pH → central chemoreception activation → ↑ ventilation

This serves two main purposes:

• 1.

  Maintenance of respiratory drive to provide sufficient tissue oxygenation.

• 2.

  Homeostatic regulation of PaCO ₂ and thus stable blood pH.

Although it has been demonstrated that peripheral chemoreceptors are primarily involved in the acute respiratory response to acidic blood pH (acidemia), central chemoreceptors may play a role in the chronic response to acidemia (see Physiology Integration Box 16.1 ).

The role of peripheral chemoreceptors

Under normal conditions, PaCO ₂ is the primary stimulus for respiratory drive in the periphery. This is because PaCO ₂ is a direct, near-linear reflection of blood CO ₂ content, whereas oxygen saturation of hemoglobin is stable for a wide range of arterial partial pressure of oxygen (PaO ₂ ) values under physiologic conditions. However, pathologically low PaO ₂ values will trigger peripheral chemoreceptors to increase ventilation (see Fast Fact Box 16.3 ).

Fast Fact Box 16.3

Recall that arterial oxygen partial pressure (PaO ₂ ) varies from 60 to 100 mm Hg while oxygen saturation remains within the 90% to 100% range.

In humans, there are two types of peripheral chemoreceptors:

• Carotid bodies

  • Located at the bifurcation of the common carotid arteries bilaterally ( Fig. 16.8 ).

    

  • Afferent impulses → glossopharyngeal nerves (CN IX) → stimulation of DRG → regulation of respiratory cycle.

• Aortic bodies

  • Located above and below the arch of the aorta (see Fig. 16.8 ).

  • Afferent impulses → vagus nerves (CN X) → stimulation of DRG → regulation of respiratory cycle.

The anatomy of the carotid and aortic bodies is designed to maximize the ability of the peripheral chemoreceptors to respond to changes in the PaO ₂ . Because of their location at areas of high arterial blood flow, each receives more than 2000 mL/100 g of tissue per minute. This means that only a negligible amount of oxygen is removed for chemoreception, and thus they can respond to true changes in PaO ₂ .

The peripheral chemoreceptors in the carotid and aortic bodies have an important role in the response to hypoxemia because they alone can increase ventilation when arterial hypo-xemia occurs. This allows them to override the normal PaCO ₂ -mediated regulation of respiration ( Fig. 16.9 ):

• Threshold for neuronal activity: PaO ₂ below 100 mm Hg

• Threshold for increased ventilation: PaO ₂ below 55 to 60 mm Hg

PaO ₂ levels below 50 mm Hg correspond to an oxygen saturation of hemoglobin below 90%—and the point at which oxygen delivery to the tissues is threatened. Any further decrease in PaO ₂ has a very potent stimulatory effect on the peripheral chemoreceptors (see Clinical Correlation Box 16.2 ).

Like the central chemoreceptors, the peripheral chemo-receptors respond to elevated PaCO ₂ by stimulating an increase in ventilation from the DRG in the medulla. The effect on ventilation is less potent than that mediated through the central chemoreceptors, but occurs 5 times faster. This allows the body to react quickly to changes in PaCO ₂ , such as during exercise. Acidic blood pH will also prompt increased ventilation by the same mechanism, to “blow off” CO ₂ and correctively raise pH to physiologic levels.

Other sensors

Even though respiration is primarily regulated by the CNS response to changes in PaCO ₂ , other mechanical and physical stimuli may modulate the rate and pattern of breathing via the stimulation of peripheral receptors.

• The Hering-Breuer reflex

  • Mediated by stretch receptors found within the smooth muscles of the small airways.

  • Stimulated by an increase in transmural pressure during lung overinflation.

  • Mechanoreception → stimulation of vagus nerve (CN X) → inhibition of medullary and pontine respiratory centers → contraction of the expiratory muscles & period of apnea (termination of breathing after end-expiration).

  • Prominent in newborns, lesser role in regulation of respiration in adults.

• J receptors

  • Named for their location in juxtaposition with capillaries in the alveolar walls.

  • Stimulated by toxins in the pulmonary circulation and by the distention of the pulmonary vessels, as can occur in pulmonary edema secondary to left heart failure.

  • Mediate tachypnea (rapid breathing) and the sensation of dyspnea (shortness of breath).

• Irritant receptors

  • Irritant and C-fiber receptor neurons are located in the epithelium of the large airways (trachea, bronchi, and bronchioles).

  • Stimulated by various noxious agents.

  • Mediate diverse reflexive responses, including coughing, sneezing, mucus secretion, and bronchoconstriction (see Clinical Correlation Box 16.3 ).

    Clinical Correlation Box 16.3

    The cough reflex is an example of how irritant receptors function to clear the airways of debris. When irritant receptors are exposed to noxious stimuli, vagal afferent nerves signal the central nervous system (CNS) respiratory centers to direct the inspiration of a large volume of air. The epiglottis and vocal cords are then closed to seal this inspired volume within the lungs. The muscles of expiration contract against this seal to generate extraordinarily high intra-pulmonary pressures. When the seal is broken as the epiglottis and vocal cords are reopened, this pressure expels the air and ideally the source of the initial noxious stimulus from the lungs. This reflex is inhibited by alcohol, which may account in part for the prevalence of aspiration pneumonia in alcoholics.

• Chest wall receptors

  • Recall: inspiratory m. contain receptors that relay information pertaining to preload (stretch before contraction) and afterload (force opposing contraction) to the CNS (see Ch. 10 ).

  • Promote reduced change in ventilation over a range of preload and afterload through reflexes occurring at the level of the spinal cord.

  • Excessive afterload (i.e., restrictive lung disease or increased airway resistance) stimulates spindle receptors and relays to CNS, resulting in the sensation of dyspnea.