Lecture 4 Control of VE Ventilatory response to CO 2 Ventilatory response to O 2 Ventilatory response to pH Ventilatory response to exercise.

Lecture 4Lecture 4

Control of VEControl of VEVentilatory response to COVentilatory response to CO22

Ventilatory response to OVentilatory response to O22

Ventilatory response to pHVentilatory response to pH

Ventilatory response to exerciseVentilatory response to exercise

Control of ventilationControl of ventilation

3 basic elements for the respiratory control 3 basic elements for the respiratory control system; SENSORS, CENTRAL CONTROLLER and system; SENSORS, CENTRAL CONTROLLER and EFFECTORS.EFFECTORS.

1- SENSOR; which gather information and feed it 1- SENSOR; which gather information and feed it to the to the →→

2- CENTRAL CONTROLLER; in the brain, which 2- CENTRAL CONTROLLER; in the brain, which coordinates the information and, in turn, sends coordinates the information and, in turn, sends impulses to the impulses to the →→

3- EFFECTORS (respiratory muscles), which cause 3- EFFECTORS (respiratory muscles), which cause ventilation.ventilation.

1)1) Central controllerCentral controllerCentral control of breathing is achieved at the brainstem, Central control of breathing is achieved at the brainstem, specially the pons and midbrain (responsible for involuntary specially the pons and midbrain (responsible for involuntary breathing) and the cerebral cortex (responsible for breathing) and the cerebral cortex (responsible for voluntary breathing).voluntary breathing).

The respiratory centre is divided into 4 groups of neurones The respiratory centre is divided into 4 groups of neurones spread throughout the entire length of the medulla and spread throughout the entire length of the medulla and pons; VRG, DRG, AC & PC.pons; VRG, DRG, AC & PC.

(1) DRG:(1) DRG:- It is located in the entire length of the dorsal aspect of the - It is located in the entire length of the dorsal aspect of the medulla.medulla.- It lies in close relation to the NTS where visceral afferents - It lies in close relation to the NTS where visceral afferents from cranial nerves IX and X terminate.from cranial nerves IX and X terminate.- It comprises inspiratory neurons. Thus, they are almost - It comprises inspiratory neurons. Thus, they are almost entirely responsible for inspiration. entirely responsible for inspiration.

(2) VRG:(2) VRG:It is located in each side of the medulla, about 5 milliliters It is located in each side of the medulla, about 5 milliliters anterior and lateral to the DRG.anterior and lateral to the DRG.They are inactive during quiet breathing, but become They are inactive during quiet breathing, but become activated during increased pulmonary ventilation, as in activated during increased pulmonary ventilation, as in exercise.exercise.They are mainly expiratory neurons with some inspiratory They are mainly expiratory neurons with some inspiratory neurons, both of which are activated when expiration neurons, both of which are activated when expiration becomes an active process.becomes an active process.They are comprises 4 nuclei;They are comprises 4 nuclei;a) the nucleus retroambigualis (NR); which is predominantly a) the nucleus retroambigualis (NR); which is predominantly expiratory with upper motor neurons passing to the expiratory with upper motor neurons passing to the expiratory muscles of the other side.expiratory muscles of the other side.b) the nucleus ambiguous (NA); which controls the dilator b) the nucleus ambiguous (NA); which controls the dilator function of larynx, pharynx and tongue.function of larynx, pharynx and tongue.c) the nucleus para-ambigualis (NP); which is mainly c) the nucleus para-ambigualis (NP); which is mainly inspiratory and control the force of contraction of the inspiratory and control the force of contraction of the inspiratory muscles of the opposite side.inspiratory muscles of the opposite side.d) the Bötzinger complex (BC); within the nucleus d) the Bötzinger complex (BC); within the nucleus rterofacialis) has widespread expiratory functions. rterofacialis) has widespread expiratory functions.

(3) AC ???:(3) AC ???:It is located in the lower pons.It is located in the lower pons.They sends excitatory impulses to the DRG of neurons and They sends excitatory impulses to the DRG of neurons and potentiates the inspiratory drive.potentiates the inspiratory drive.It receives inhibiting impulses from the sensory vagal fibers It receives inhibiting impulses from the sensory vagal fibers of the Hering-Breuer inflation reflex and inhibiting fibers of the Hering-Breuer inflation reflex and inhibiting fibers from the pneumotaxic centre in the upper pons.from the pneumotaxic centre in the upper pons.

(4) PC;(4) PC;It is located dorsally in the upper pons.It is located dorsally in the upper pons.It transmits inhibitory impulses to the AC and to the It transmits inhibitory impulses to the AC and to the inspiratory areas to switch off inspiration.inspiratory areas to switch off inspiration.The function of this centre is primarily to limit inspiration. The function of this centre is primarily to limit inspiration. This has a secondary effect of increasing the rate of This has a secondary effect of increasing the rate of breathing.breathing.Some investigators believed that the role of this centre is Some investigators believed that the role of this centre is “fine tuning” of respiratory rhythm because a normal “fine tuning” of respiratory rhythm because a normal rhythm can exist in the absence of this centre. rhythm can exist in the absence of this centre.

2) Effectors2) EffectorsThey are the muscles of respiration, including the They are the muscles of respiration, including the diaphragm, intercostals muscles, abdominal muscles diaphragm, intercostals muscles, abdominal muscles and accessory muscles as sternocleidomastoid.and accessory muscles as sternocleidomastoid.

It is crucially important that these various muscle It is crucially important that these various muscle groups work in a coordinated manner, and this is the groups work in a coordinated manner, and this is the responsibility of the central controller.responsibility of the central controller.

There is some evidence that some newborn children, There is some evidence that some newborn children, particularly those who are premature, have particularly those who are premature, have uncoordinated respiratory muscle activity, especially uncoordinated respiratory muscle activity, especially during sleep. For example, the thoracic muscle may during sleep. For example, the thoracic muscle may try to inspire while the abdominal muscle expire. This try to inspire while the abdominal muscle expire. This may be a factor in the “sudden infant death may be a factor in the “sudden infant death syndrome” (SIDS).syndrome” (SIDS).

3) Sensors3) SensorsThe sensors that contribute to the control of breathing The sensors that contribute to the control of breathing include;include;- lung stretch receptors in the smooth muscle of the - lung stretch receptors in the smooth muscle of the airway, (SAR)airway, (SAR)- irritant receptors located between airway epithelial - irritant receptors located between airway epithelial cells, (RAR)cells, (RAR)- joint and muscle receptors that stimulate breathing - joint and muscle receptors that stimulate breathing in response to limb movement, and in response to limb movement, and - juxtacapillary (or J) receptors located in alveolar - juxtacapillary (or J) receptors located in alveolar walls which sense engorgement of the pulmonary walls which sense engorgement of the pulmonary capillaries and cause rapid shallow breathing. capillaries and cause rapid shallow breathing. 

The most important sensors are central The most important sensors are central chemoreceptors in the medulla as well as peripheral chemoreceptors in the medulla as well as peripheral chemoreceptors in the carotid and aortic bodies.  chemoreceptors in the carotid and aortic bodies.  

Central chemoreceptors (CC)Central chemoreceptors (CC)

They are most probably located on the ventrolateral They are most probably located on the ventrolateral surfaces of the medulla oblongata, which bathed CSF.surfaces of the medulla oblongata, which bathed CSF.

The CCs in the medulla respond to changes in the pH The CCs in the medulla respond to changes in the pH of the CSF.  A of the CSF.  A ↓↓ in CSF pH in CSF pH →→ ↑↑ in breathing in breathing (hyperventilation) whereas (hyperventilation) whereas ↑↑ in pH in pH →→ hypoventilation. hypoventilation.

They are highly sensitive to [HThey are highly sensitive to [H++] of the CSF evoked by ] of the CSF evoked by PaCOPaCO22, since CO, since CO22 can freely cross the blood-brain can freely cross the blood-brain barrier into the CSF while the barrier is relatively barrier into the CSF while the barrier is relatively impermeable to Himpermeable to H++ and H and H22COCO33..

Stimulation of these receptors increases both the rate Stimulation of these receptors increases both the rate of rise and the intensity of the inspiratory signals, of rise and the intensity of the inspiratory signals, thereby increasing the frequency of the respiratory thereby increasing the frequency of the respiratory rhythm. rhythm.

Peripheral chemoreceptors (PC)Peripheral chemoreceptors (PC)They are located in the carotid bodies at the bifurcation of the They are located in the carotid bodies at the bifurcation of the common carotid arteries and in the aortic bodies above and common carotid arteries and in the aortic bodies above and below the aortic arch.below the aortic arch.

They cause an They cause an ↑↑ in V in VEE in response to in response to ↓↓ in PaO in PaO22, , ↑↑ in PaCO in PaCO22 and and ↑↑ in in arterial [Harterial [H++] (] (↓↓ in pH). in pH).

The carotid bodies are most important in humans. They contain The carotid bodies are most important in humans. They contain glomus cells of two or more types which show an intense glomus cells of two or more types which show an intense fluorescence staining because of their large content of dopamine.fluorescence staining because of their large content of dopamine.

The mechanism of chemoreception is not yet understood. A The mechanism of chemoreception is not yet understood. A popular view has been that glomus cells themselves are popular view has been that glomus cells themselves are chemoreceptors.chemoreceptors.

They are highly sensitive to changes in PaOThey are highly sensitive to changes in PaO22 and to a lesser extent and to a lesser extent to PaCOto PaCO22 and pH. They are also sensitive to temp of the blood and and pH. They are also sensitive to temp of the blood and BF. (HOW)?BF. (HOW)?

The response of the PCs to PaCOThe response of the PCs to PaCO22 is much less important than that is much less important than that of the CCs.of the CCs.

Lung and airway receptorsLung and airway receptorsReceptors in the lung and airways are innervated by myelinated Receptors in the lung and airways are innervated by myelinated and unmyelinated vagal fibers. and unmyelinated vagal fibers. The unmyelinated fibers are C fibers.The unmyelinated fibers are C fibers.The myelinated fibers are commonly divided into SARs and RARs The myelinated fibers are commonly divided into SARs and RARs on the basis of whether sustained stimulation leads to prolonged on the basis of whether sustained stimulation leads to prolonged or transient discharge in their afferent fibers.or transient discharge in their afferent fibers.SARs are also known as pulmonary stretch receptors.They are SARs are also known as pulmonary stretch receptors.They are thought to participate in ventilatory control by prolonged thought to participate in ventilatory control by prolonged inspiration in conditions that reduce lung inflation.inspiration in conditions that reduce lung inflation. RARs are stimulated by chemicals such as histamine, dust, RARs are stimulated by chemicals such as histamine, dust, cigarette smoke. Therefore, they have been called irritant cigarette smoke. Therefore, they have been called irritant receptors.receptors.Activation of RARs in the lung may produce hyperpnea.Activation of RARs in the lung may produce hyperpnea.Activation of RARs in the trachea causes coughing, Activation of RARs in the trachea causes coughing, bronchoconstriction & mucus secretion.bronchoconstriction & mucus secretion.

J receptors are stimulated by hyperinflation of the lung. They J receptors are stimulated by hyperinflation of the lung. They respond to intravenous & intracardiac administration to chemicals respond to intravenous & intracardiac administration to chemicals such as capsaicin. They play a role in the dyspnea associated with such as capsaicin. They play a role in the dyspnea associated with left heart failure, interstitial lung disease, pneumonia and left heart failure, interstitial lung disease, pneumonia and microembolism. microembolism.

The Hering-Breuer reflexes thought to play a major role in The Hering-Breuer reflexes thought to play a major role in VVEE by determining the rate and depth of breathing. This can by determining the rate and depth of breathing. This can be done by using the information from the SARs to be done by using the information from the SARs to modulate the “switching off” mechanism in the medulla. modulate the “switching off” mechanism in the medulla.

The Hering-Breuer inflation reflex is an ↑ in the duration of The Hering-Breuer inflation reflex is an ↑ in the duration of expiration produced by steady lung inflation, and the expiration produced by steady lung inflation, and the Hering-Breuer deflation reflex is a ↓in the duration of Hering-Breuer deflation reflex is a ↓in the duration of expiration produced by marked deflation of the lung.expiration produced by marked deflation of the lung.

In human beings, the Hering-Breuer reflex probably is not In human beings, the Hering-Breuer reflex probably is not activated until Vactivated until VTT ↑↑ to more than three times normal (i.e. < to more than three times normal (i.e. < 1.5 l/breath). Therefore, this reflex appears to be mainly a 1.5 l/breath). Therefore, this reflex appears to be mainly a protective mechanism for preventing excess lung inflation protective mechanism for preventing excess lung inflation rather than an important ingredient in normal control of VE. rather than an important ingredient in normal control of VE.

Ventilatory response to COVentilatory response to CO22

The most important factor in the control of VThe most important factor in the control of VEE is is PaCOPaCO22..

The VR to COThe VR to CO22 is normally measured by having the is normally measured by having the subject inhale COsubject inhale CO22 mixture or rebreathe from a bag mixture or rebreathe from a bag so that the inspired PCOso that the inspired PCO22 gradually ↑. gradually ↑.

With a normal POWith a normal PO22 the V the VEE ↑ by about 2-3 l/min for ↑ by about 2-3 l/min for each 1 mmHg rise in PCOeach 1 mmHg rise in PCO22. Lowering the PO. Lowering the PO22 produces 2 effects; (see the figure)produces 2 effects; (see the figure)1) there is a higher V1) there is a higher VEE for a given PCO for a given PCO22

2) the slope of the line becomes steeper.2) the slope of the line becomes steeper.

The VR to COThe VR to CO22 is reduced by sleep, ↑ age, and is reduced by sleep, ↑ age, and genetic, racial and personality factors. It can also genetic, racial and personality factors. It can also be reduced if the work of breathing is ↑. be reduced if the work of breathing is ↑.

Ventilatory response to OVentilatory response to O22

The way in which a reduction of PaOThe way in which a reduction of PaO22 stimulates stimulates VE can be studied by having the subject breathe VE can be studied by having the subject breathe hypoxic gas mixture.hypoxic gas mixture.

An ↑ in PCOAn ↑ in PCO22 → → ↑↑ V VEE at any PO at any PO22. . When the PCOWhen the PCO22 is is ↑ a reduction in PO↑ a reduction in PO22 below 100 mmHg causes below 100 mmHg causes some stimulation of Vsome stimulation of VEE..

Hypoxemia reflexly stimulates VHypoxemia reflexly stimulates VEE by its action on by its action on the carotid and aortic body chemoreceptors.the carotid and aortic body chemoreceptors.

Ventilatory response to pHVentilatory response to pH

A reduction in arterial blood pH stimulates VA reduction in arterial blood pH stimulates VEE..

Patients with a partly compensated metabolic Patients with a partly compensated metabolic acidosis, such as diabetes mellitus, who have a acidosis, such as diabetes mellitus, who have a low pH and Low PCOlow pH and Low PCO22 shown an ↑ in V shown an ↑ in VEE..

The chief site of action of a reduced arterial pH is The chief site of action of a reduced arterial pH is the PCs, especially the carotid bodies in humans. the PCs, especially the carotid bodies in humans. It is also possible that the CCs or the respiratory It is also possible that the CCs or the respiratory center itself is affected by a change in blood pH if center itself is affected by a change in blood pH if

it is large enough.it is large enough.

Ventilatory response to exerciseVentilatory response to exerciseOn exercise, VOn exercise, VEE ↑ promptly and, during strenuous exercise, it may ↑ promptly and, during strenuous exercise, it may reach very high levels.reach very high levels.

The ↑ in VE closely matches the ↑ in VOThe ↑ in VE closely matches the ↑ in VO22 and VCO and VCO22..

The PaCOThe PaCO22 does not ↑ during most form of exercise, however, does not ↑ during most form of exercise, however, during sever exercise it falls slightly.during sever exercise it falls slightly.The PaOThe PaO22 ↑ slightly, and it may fall at very high work levels. ↑ slightly, and it may fall at very high work levels.The arterial pH remains nearly constant for moderate exercise, The arterial pH remains nearly constant for moderate exercise, and falls during heavy exercise.and falls during heavy exercise.

Factors which play a role in the ↑ in VFactors which play a role in the ↑ in VEE during exercise includes; during exercise includes;- ↑ body temperature- ↑ body temperature- ↑ plasma epinephrine conc- ↑ plasma epinephrine conc- ↑ plasma potassium conc- ↑ plasma potassium conc- ↑ CO- ↑ CO22 load to the lung load to the lung- Passive movement of the limbs - Passive movement of the limbs