Control of Ventilation

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

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

Cortex

• Breathing is also under voluntary control, and the brainstem control can be overridden (to some extent)
• P_CO2 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

Effectors

• 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

Sensors

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 P_CO2 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 P_CO2

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 P_O2, pH, and P_CO2
• 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 P_O2 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 P_CO2
• Carotid but not aortic bodies respond to a fall in arterial pH . Both respond to P_O2 and P_CO2 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:

• P_CO2 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 P_O2, ventilation increases by 2 to 3 L/min for each mmHg rise in P_CO2
• Lowering P_O2 causes increased ventilation for a given P_CO2, as well as producing a steeper ventilatory response to increasing P_CO2

• 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 P_CO2 and decreasing pH

Response to Oxygen:

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

• If P_CO2 kept to 36mmHg, P_O2 can be reduced to ~50mmHg before increase in ventilation occurs
• Raising P_CO2 increases ventilation at any P_O2

• 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 P_O2 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 P_CO2
• 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 P_CO2, causing continual overshooting of respiration in both directions

Pregnancy

• 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 P_CO2 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