Chemical Control of Breathing

Body works to maintain proper levels of O2, CO2, and pH through mediation of chemoreceptors as it affects VE


Central chemoreceptors

fig 9-3.jpg

Fig. 9-3.  The relationship of the blood-brain barrier (BBB) to CO2, HCO3, and H+. CO2 readily crosses the BBB. H+ and HCO3 do not readily cross the BBB. H+ and HCO3 require the active transport system to cross the BBB.  CSF = cerebrospinal fluid.


Located bilaterally in the medulla

Stimulated directly by H+ ions in the cerebrospinal fluid, indirectly by CO

The BBB is almost impermeable to H+ and HCO3 but CO2 freely crosses from the blood to the cerebrospinal fluid.

In CSF, CO2 is hydrolized, releasing H+.

An increased CO2 therefore increases H+ in CSF which stimulates the neurons to cause hyperventilation to restore normal levels pH and CO2.

increased 2–3 L/min for 1–mm Hg rise in PaCO2.

In normal circumstances our primary stimulus to breaths is PaCO2. This is an important point to remember as it is not unusual for patients on mechanical ventilation to be over-ventilated. If their CO2 is less than the level it takes to stimulate the central chemoreceptors then they will not initiate a breath on their own, and this can be misinterpreted as an apneic period.

Peripheral chemoreceptors

Located in the aortic arch and bifurcations of common carotid arteries

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Fig. 9-4.  Location of the carotid and aortic bodies (the peripheral chemoreceptors).


Peripheral chemoreceptors' response to ⇓ PaO2

The carotid bodies more responsive to a decrease in PaO2 than the aortic bodies.

This response is frequently referred to as the "Hypoxic drive" however current research indicates that Hhypoxemia increases receptors sensitivity for H+, and it is this that stimulates a increse in minute ventilation.

⇓PaO2 causes ⇑ for any pH, and vice versa.

In severe alkalosis, hypoxemia has little affect on .


Only affected by PaO2, not CaO2 (so in conditions such as anemia or COHb, even though the patient's total O2 content is reduced, the periperhal chemoreceptor's are not stimulated)

Not a significant response until PaO2 falls to ~60 mm Hg (corresponds to an SaO2 of 90%) A further fall results in sharp increase in VE. However this response limits out at a PaO2 of 30 mm Hg, with suppression of respiration occuring below that level.

This means the under normal circumstances, oxygen plays no role in drive to breathe.

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Fig. 9-5.  Schematic illustration showing how a low PaO2 stimulates the respiratory components of the medulla to increase alveolar ventilation.


Once the PaO2 fall to 60 then, hypoxemia is the most common cause of hyperventilation.

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Fig. 9-6.  The effect of low PaO2 levels on ventilation.


Peripheral chemoreceptors' response to ⇑PaCO2 and [H+] - 20 to 30% of the ventilatory response to hypercapnia.

Less responsive than central chemoreceptors (CCRs)

One-third of hypercapnic response, but a more rapid response to changes in [H+]

Influenced by fixed acids such as Lactic acid, ketones

In hyperoxia, PCRs are almost totally insensitive to changes in PaCO2, so any response is due to CCRs responding to changes in CSF [H+].

Low PaCO2 renders PCRs almost unresponsive to ⇓PaO2.

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Fig. 9-7.  The effect of PaO2 on ventilation at three different PaCO2 values. Note that as the PaCO2value increases, the sensitivity of the peripheral chemoreceptors increases.


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Fig. 9-8.  The accumulation of lactic acids leads to an increased alveolar ventilation primarily through the stimulation of the peripheral chemoreceptors. 

Coexisting acidosis, hypercapnia, and hypoxemia maximally stimulate PCRs

Low PaCO2 renders PCRs almost unresponsive to ⇓PaO2

PCR are also stimulated by:

Hypoperfusion (stagnant or circulatory hypoxia)

Increased temperature

Nicotine - which also causes

Peripheral vasoconstriction

Increased pulmonary vascular resistance

Systemic arterial hypertension


Increased left ventricular performance

Control of breathing in chronic hypercapnia

A sudden rise in PaCO2 in the normal person causes an immediate rise in VE. In slow-rising PaCO2 (such as seen in the development of severe COPD), the kidneys retain HCO3–, which maintains CSF pH, so no hyperventilation response is trigger by the chronically elevated CO2.

Hypoxemia seen with hypercapnia becomes the minute-to-minute breathing stimulus via altered response to [H+].

Hypoxemia is always present in severe COPD due to severe mismatches in V/Q.

An increased FIO2 raises the PaO2 making the PCR less sensitive to [H+] resulting in a higher PaCO2

Oxygen-induced hypercapnia

O2 therapy may cause a sudden rise in PaCO2 in severe COPD with chronic hypercapnic. This rise in CO2 may be significant enough to cause a condition known as CO2 narcosis - the patient becomes obtunded and non-responsive, further hypoventilation occurs, and can lead to coma and death.

Possible explanations include

Hypoxic drive is removed (traditional view).

⇑FIO2 may worsen V/Q mismatch

Hypoxic pulmonary vascoconstriction is reversed to poorly ventilated alveoli

⇑FIO2 may make patient susceptible to absorption atelectasis.

hypvaso.jpg hypvaso2.jpg

A. Low V/Q unit: Hypoxia and hypercapnia on room air (0.21) causes pulmonary vasocontriction which directs blood to alveolus with better ventilation.

B. Increased FIO2 to 0.50 results in absorbtion atelectasis in poorly ventilated unit which further diminishes ventilation while blood flow (perfusion) is increased due to the relief of hypoxic vasoconstriction. This results in further V/Q imbalances: redistributes blood flow to underventilated unit, and ventilation to already well-ventilated unit which is now receiving less perfusion (increased dead space)

Oxygen-induced Hypercapnia: KEY POINTS

The diagnosis of "COPD" does NOT signify chronic hypercapnia or that O2 therapy will induce hypoventilation. Only an arterial blood gas can show CO2 retention and compensation by the kidneys.

These characteristics are only in end-stage disease.

Present in small percent of COPD patients

 Concern about O2-induced hypercapnia and acidemia is not warranted in most COPD patients.

 O2 should NEVER be withheld in hypoxemic COPD patients as tissue oxygenation is an overriding priority.

 Be prepared to provide MV to the rare COPD patient who does have severe hypoventilation due to oxygen therapy.

CCR response to acute CO2 increase in chronic hypercapnia

Acute rises in PaCO2 continues to stimulate the CCRs.

Resulting ventilatory response is depressed due to chemical and mechanical reasons.

Increased HCO3– prevents as large a fall in pH, as would be seen in a healthy patient.

Abnormal mechanics impair lung ability to increase VE.

Ventilatory Response to Exercise

Strenuous exercise can increase CO2 production and O2 consumption 20-fold.

Ventilation normally keeps pace so all ABG values are held constant.

Mechanism for increased VE poorly understood: may be

CNS sends concurrent signals to skeletal muscles and to medullary respiratory centers.

Joint movement stimulates proprioceptors, which send excitatory signals to medullary centers.

May also be due to repeated experience causing anticipatory changes in ventilation

fig 9-9.jpg

Fig. 9-9.  The respiratory center coordinates signals from the higher brain region, great vessels, airways,
lungs, and chest wall. (+) = increased ventilatory rate; (-) = decreased ventilatory rate.