Control of Ventilation

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3 basic elements in the respiratory control system:

  • Sensors - gather information and feed it to the
  • Central Controller - coordinates the information and sends impulses to the
  • Effectors (respiratory muscles) - which cause ventilation

This is a negative feedback system - increased effector activity generally decreases sensory input

Neurogenesis of Breathing[edit]

Respiratory centres mainly act via the phrenic nerves, but also send impulses to other respiratory muscles

Medullary Respiratory Centres

  • Lie within the reticular formation of the brainstem
  • Two poorly localised groups:
  • Dorsal respiratory group (DRG) - inspiration
  • Ventral respiratory group (VRG) - expiration +/- inspiration
  • Cells within the DRG have an inherent rhythmicity - generate bursts of neuronal activity to the diaphragm and respiratory muscles without any input
  • DRG controlled by the pneumotaxic centre which terminates the inspiratory "ramp" of action potentials, limiting inspiration and increasing respiratory rate
  • VRG expiratory area is quiescent during normal quiet breathing, however becomes active in more forceful breathing

Apneustic Centre

  • In lower pons
  •  ? If active in normal human respiration
  • Promotes inspiration in DRG
  • If brain sectioned above it, results in apneustic respiration - deep, gasping inspiration with a pause at full inspiration followed by brief, insufficient release

Pneumotaxic Centre

  • In upper pons
  • Regulates inspiration volume by inhibition of inspiratory DRG, and secondarily, respiratory rate
  • Respiratory rhythm exists without this centre, but it is important in fine-tuning ventilation


  • Breathing is also under voluntary control, and the brainstem control can be overridden (to some extent)
  • PCO2 can be halved causing alkalosis and tetany with contraction of the muscles of the hand and foot without much difficulty
  • Voluntary hypoventilation is more difficult - breath holding duration is limited by PCO2, PO2 and other factors
  • Hyperventilation before breath-holding extends breath-hold time
  • The physical act of breathing also extends breath-holding time, even if it is breathing a hypoxic/hypercapnic gas mixture

The limbic system and hypothalamus can also alter breathing pattern, eg. in emotional states


  • Diaphragm, intercostal muscles, abdominal muscles, accessory muscles
  • Crucial that the central control centre activates these muscles in a coordinated fashion
  • Some newborn children have uncoordinated resp muscle activity, esp. during sleeping - ?link to SIDS


Central Chemoreceptors

  • Most important are situated near the medullary ventral surface, adjacent to exit points of 9th/10th nerves
  • Local application of H+ or dissolved CO2 stimulates breathing within seconds
  • Surrounded by brain ECF and respond to changes in H+ concentration - increased H+ stimulates, decreased H+ inhibits
  • Brain ECF concentration is governed primarily by CSF, then by local blood flow and local metabolism
  • CSF is separated from blood by the blood brain barrier - impermeable to H+ and HCO3- ions, but easily permeable to CO2
  • When PCO2 increases, CO2 diffuses into CSF and liberates H+ ions
  • Normal CSF pH 7.32, and CSF has much lower buffering capacity than blood so pH will fluctuate more with variation on blood CO2
  • CSF also buffers pH by changing HCO3- levels, and achieves this more rapidly than it occurs in systemic circulation renal compensation
  • Patients with chronic lung disease, or those exposed to 3% CO2 for some days readjust their pH to near normal levels which results in abnormally low ventilation for their arterial PCO2

Peripheral Chemoreceptors

  • Located in the carotid bodies at the bifurcation of the common carotid arteries, and in the aortic bodies above and below the aortic arch
  • The carotid bodies are most important in humans
  • Contain glomus cells of 2 types:
  • Type I cells - large dopamine content, therefore stain intensely. Closely apposed to endings of the afferent carotid sinus nerve.
  • Type II cells - rich capillary supply.
  • Release of neurotransmitters from glomus cells affects carotid body afferent nerve fibre discharge
  • Respond to PO2, pH, and PCO2
  • Sensitivity to arterial PO2 begins at 500mmHg, but really increases below 50-100mmHg
  • Very high blood flow relative to their size, so although they have a high metabolic rate, the arterial-venous O2 difference is minimal
  • Respond to arterial PO2 rather than venous
  • Responsible for ALL increase in ventilation due to arterial hypoxemia, and if these receptors are removed severe hypoxia may depress ventilation
  • Peripheral response to PCO2 is less important than that of the central chemoreceptors - less than 20% of the response of central receptors, although more rapid than central receptors and may be useful in compensating for abrupt changes PCO2
  • Carotid but not aortic bodies respond to a fall in arterial pH . Both respond to PO2 and PCO2 changes.

Lung Receptors

  • Pulmonary stretch receptors:
  • Lie within airway smooth muscle
  • Discharge in response to lung distension, sending impulses in vagus nerve via large myelinated fibres
  • Reflex effect of stimulation is the Hering-Breuer inflation reflex which slows respiratory frequency by increasing expiration time
  • Deflation of lungs also initiates inspiratory activity via the deflation reflex
  • Reflexes largely inactive unless tidal volume exceeds 1 litre (eg. in exercise), or in newborn babies
  • Irritant Receptors (or rapidly adapting pulmonary stretch receptors)
  • Lie between airway epithelial cells
  • Stimulated by noxious gases, cigarette smoke, inhaled dusts and cold air
  • Impulses travel up the vagus in myelinated fibres
  • Reflex effects are bronchoconstriction and hyperpnea
  • Adapt rapidly and are involved in other mechanoreceptor functions
  • Likely play a role in asthma bronchoconstriction via histamine release
  • Also irritant receptors in nose/nasopharynx, larynx and trachea causing various reflexes including sneezing, coughing, broncho constriction and laryngeal spasm
  • J (juxtacapillary) Receptors:
  • Endings of non-myelinated C fibres
  • In the alveolar walls, close to capillaries
  • Respond very quickly to chemicals injected into pulmonary circulation
  • Impulses travel in slow conducting nonmyelinated fibres in the vagus nerve
  • Stimulation causes rapid, shallow breathing. Intense stimulation causes apnea.
  • Pulmonary capillary engorgement and increases in interstitial fluid volume activate these receptors
  • May be involved in left heart failure and interstitial lung disease
  • Bronchial C fibres:
  • Supplied by bronchial circulation (not pulmonary circulation like the J receptors)
  • Reflex response include rapid, shallow breathing, bronchoconstriction and mucous secretion
  • Joint and muscle receptors stimulate ventilation in exercise
  • Gamma system spindles - in intercostals, diaphragm and other muscles - sense strength of contraction and may be involved in dyspnoea that occurs when lots of respiratory effort is required to move the lung and chest wall eg. in airway obstruction
  • Arterial baroreceptors - increase in arterial BP can cause reflex hypoventilation or apnea via aortic/carotid sinus baroreceptor stimulation. Decreased BP can result in hyperventilation
  • Pain/temperature - stimulation of these nerves can bring about changes in ventilation

Response to Carbon Dioxide:

  • PCO2 of arterial blood is the most important factor controlling ventilation - held within 3mmHg during the day
  • Response to CO2 measured by subject rebreathing from CO2 enriched bag:
  • With normal PO2, ventilation increases by 2 to 3 L/min for each mmHg rise in PCO2
  • Lowering PO2 causes increased ventilation for a given PCO2, as well as producing a steeper ventilatory response to increasing PCO2

Screen shot 2012-09-12 at 7.31.26 PM.png

  • Respiratory drive can also be measured by recording inspiratory pressure for a brief period of airway occlusion, provided by a valve box which occludes for the first 0.5 seconds of inspiration. Pressure generated during the first 0.1 seconds of attempted inspiration is the respiratory center output.
  • Hyperventilation diminishes respiratory drive, and an over-ventilated patient pay take a minute to breathe after being overventilated
  • Ventilatory response to CO2 is:
  • Reduced by sleep, age, genetic/racial/personality factors, athletic/dive training, morphine and barbituates
  • Also reduced if work of breathing is increased, eg. if a subject breathes through a narrow tube. Neural respiratory drive output is not reduced, but is just not as effective in producing ventilation. This is partly why COPD patients chronically retain CO2
  • CO2 response is mostly mediated via the central chemoreceptors in response to falling pH in brain ECF, and secondarily by rising PCO2 and decreasing pH

Response to Oxygen:

  • Ventilatory response to oxygen is measured by having the patient breathe hypoxic gas mixtures

Screen shot 2012-09-12 at 7.54.00 PM.png

  • If PCO2 kept to 36mmHg, PO2 can be reduced to ~50mmHg before increase in ventilation occurs
  • Raising PCO2 increases ventilation at any PO2
  • Combined effect of both high CO2 and low O2 is greater than the individual effects of each
  • PO2 does not affect day-to-day ventilation much as it rarely reaches low levels
  • Important at altitude, and in patients with severe lung disease:
  • In chronic, severe lung disease, ECF pH has returned to normal despite high CO2, therefore these patients lose most of their CO2 ventilation stimulus
  • In this case, giving high PO2 mixtures can result in severely depressed ventilation
  • Hypoxic response is all through peripheral chemoreceptors

Response to pH:

  • Reduction in arterial blood pH stimulates ventilation
  • Patients who have low pH for metabolic reasons hyperventilate to raise pH, even while decreasing PCO2
  • Main site of reduced arterial pH response is peripheral chemoreceptors
  • Central chemoreceptors can be directly affected by a large enough blood pH - if pH very low, blood-brain barrier becomes partly permeable to H+ ions

Cheyne-Stokes respiration

  • Periods of apnea lasting 10 - 20 seconds, followed by equal periods of hyperventilation with variable tidal volume
  • Seen often at high altitude, especially during sleep. Also in severe heart disease or brain damage.
  • Reproduced in animals by lengthening distance blood travels to reach brain causing long delay before chemoreceptors sense changes in PCO2, causing continual overshooting of respiration in both directions


  • Minute ventilation increases, up to 50% increase at term
  • Increase in TV and respiratory rate
  • Progesterone stimulates respiratory centre causing a left shift in ventilation/C02 response curve - PC02 26 – 32mmHg by 1st trimester
  • Restored to normal rapidly post delivery
  • During labour minute ventilation further increases due to pain. Contractions increase 02 consumption
  • After contractions hypocapnic (transient) hypoventilatory period that can lead to desaturation

Effect of Anaesthesia on Respiration

  • Inhaled anaesthetics, barbituates and opioids reduce sensitivity to CO2 as well as (volatiles especially) reducing response to hypoxia (via carotid body chemoreceptors)
  • Ventilation/CO2 curve is flattened
  • Apnoeic threshold is increased, therefore high PCO2 required to kick-start ventilation after hyperventilation
  • Rib cage excursions diminish with deepening anaesthesia, which reduces ventilatory response produced by intercostal muscles, causing decreased CO2 sensitivity
  • The effects of anaesthetic agents persist into the early post-operative period, therefore prolonged risk of hypoxia or hypoventilation