Control of breathing Flashcards
Where is the chemoreceptor for respiratory drive in the carotid? Anatomically and histologically
Body/glomus
adventitia
What are the cells in the carotid body which are chemoreceptors?
Type 1 glomus cells - neuronal in origin
How do chemoreceptors detect changes
◦ Sense oxygen —> potassium channels involved —> depolarisation and synaptic NT release to stimulate glossopharyngeal
What oxygen stimulus do the carotid body glomus cells respond to
PaO2 NOT oxygen delivery
i.e. in conditions of lack of oxygen availability but high PaO2 (methaemoglobinaemia, carbon monoxide poisoning there is no firing)
Stimulus for carotid body respiratory drive 5
PaO2, PaCO2, pH, temperature, hypoglcyaemia
Which is more sensitive to PaCO2 - peripehral or central
◦ Less sensitive to PCO2 than central receptors - contributes 20% or so to PCO2 changes of respiration, it is perhaps more rapid than the central CO2 sensing though (1-3 seconds vs 10 seconds)
Afferent from carotid body chemoreceptors
glossopharyngeal
Aortic glomus cells are located where? Where do their cell bodies lie
- Aortic arch, subclavian arteries and pulmonary trunk
◦ Cell bodies sitting in the Stellate ganglion
◦ Historically identical to carotid glomus but receive 1/6 of the blood supply of the carotid and scattered as small groups of cells
Which of the two chemoreceptors responds to oxygen content
aortic - so they do respond to anaemia
How is the stimulus different for activation of aortic chemoreceptors compared to carotid body
◦ They sense oxygen content feather than oxygen tension (although respond weakly too rhe latter)
◦ This is why they respond to anaemia, carboxyhaemoglobin and hypotension even where the PaO2 may be the same
* Stimulus - Pa O2, change in O2 delivery (anaemia, carboxyhaemoglobin, hypotension), PaCO2 to an extent. Not to BSL or temp or pH though
Afferent from aortic chemoreceptors
aortic nerve of the vagus
What is the most important respiratory sensor for minute to minute ventilation
Central receptor - ventral medulllary sensing body
ventrolateral medulla around the origin of the 9th aand 10th cranial nerve
What does the central controller measure
Ventrolateral medullary central sensor body - extracellular fluid –> intracellualr fluid affcted
Minimal CSF buffering so small changes are rapidly adjusted for
Stimulus for ventrolateral medullary sensing body
pH of the CSF (NOT PCO2)
PCO2 indirectly chnages CSF pH –> intacellular pH changes leading to a response
Unknown method of signal transduction
Give 3 examples of lung receptors
Mechanoreceptors - slowly adapting pulmonary srretch receptors, stimulate activity when defleated and depress when overstretched.
Irritant fibres
* Respond to cold air, smoke, certain gasses
* May potentially have some rapidly adapting stretch receptor action
* Trigger bronchoconstriction
J receptors and bronchial C fibres
* J receptors - The sit juxtacapillary and monitor the blood
◦ Cause rapid shallow breathing
◦ E.g. in pulmonary oedema —> stimulates these receptors; or in interstitial lung disease
* Bronchial C fibres sit next to bronchial vessels
◦ Similar to above
◦ But supply the bronchial circulation
Other
* Nose and upper airway - irritant receptors, can cause bronchoconstriction
* Joints and muscles - exercise induced increase in ventilation
* Gamma system - sensing elongation of muscles, sensation of dyspnoea potentially produced from here
* Arterial baroreceptors - anatomically close to the peripheral chemoreceptors, ventilatory response to PaO2 is reduced in space
* Pain and temperature
What is a J receptor in the lung
- J receptors - The sit juxtacapillary and monitor the blood
◦ Cause rapid shallow breathing
◦ E.g. in pulmonary oedema —> stimulates these receptors; or in interstitial lung disease
Where are pulmonary mechanoreceptors
In the walls of bronchi
Are pulmonary stretch receptors rapidly or slowly adapting
SLowly adapting
What is the Hering Breuer reflex
Overinflation of the lung stops further inflation
Additionally inflation of the lung depresses vagal neurons of the nucleus ambiguous resulting in increased HR and decreased RR with inflation, maintains stable BP and HR in the face of hypoxia and hypercapnoea
What are the two major respiratory groups in the brainstem
The ventral and dorsal medullary respiratory groups
What is the dorsal medullary respiratory groups function? Where is it? What is it close to?
◦ Primarily involved in timing of the respiratory cycle
◦ Inspiration - UMN axons to contralateral anterior horn cells controlling inspiratory muscles
◦ Lies in close relation to the nucleus tractus solitarius where visceral afferents from CN 9 and 10 terminate
What is the ventral respiratory group made up of? (4)
‣ Caudal ventral respiratory group -
* Nucleus retroambigualis
◦ Expiratory
◦ UMN passing to contralteral expiratory muscles
* Nucleus para-ambigualis
◦ Inspiratory
◦ Force of contraction of contralteral inspiratory muscles
‣ Rostral ventral respiratory group
* Nucleus ambiguous
◦ Airway dilator functions of the larynx, pharynx and tongue
‣ Pre-Botzinger
* Central pattern generator is primarily located here but groups of neutrons are spread throughout the medulla
‣ Botzinger
* Within the nucleus retrofacialis
* Expiratory functions
What is the Botzinger complex? How does it related to toher respiratory groups>q
‣ Caudal ventral respiratory group -
* Nucleus retroambigualis
◦ Expiratory
◦ UMN passing to contralteral expiratory muscles
* Nucleus para-ambigualis
◦ Inspiratory
◦ Force of contraction of contralteral inspiratory muscles
‣ Rostral ventral respiratory group
* Nucleus ambiguous
◦ Airway dilator functions of the larynx, pharynx and tongue
‣ Pre-Botzinger
* Central pattern generator is primarily located here but groups of neutrons are spread throughout the medulla
‣ Botzinger
* Within the nucleus retrofacialis
* Expiratory functions
What is the pre-Botzinger complex and how does it related to toher respiratory groups
‣ Caudal ventral respiratory group -
* Nucleus retroambigualis
◦ Expiratory
◦ UMN passing to contralteral expiratory muscles
* Nucleus para-ambigualis
◦ Inspiratory
◦ Force of contraction of contralteral inspiratory muscles
‣ Rostral ventral respiratory group
* Nucleus ambiguous
◦ Airway dilator functions of the larynx, pharynx and tongue
‣ Pre-Botzinger
* Central pattern generator is primarily located here but groups of neutrons are spread throughout the medulla
‣ Botzinger
* Within the nucleus retrofacialis
* Expiratory functions
What is the rostal ventral respiratory groups function
‣ Caudal ventral respiratory group -
* Nucleus retroambigualis
◦ Expiratory
◦ UMN passing to contralteral expiratory muscles
* Nucleus para-ambigualis
◦ Inspiratory
◦ Force of contraction of contralteral inspiratory muscles
‣ Rostral ventral respiratory group
* Nucleus ambiguous
◦ Airway dilator functions of the larynx, pharynx and tongue
‣ Pre-Botzinger
* Central pattern generator is primarily located here but groups of neutrons are spread throughout the medulla
‣ Botzinger
* Within the nucleus retrofacialis
* Expiratory functions
What is the caudal respiratory groups function
‣ Caudal ventral respiratory group -
* Nucleus retroambigualis
◦ Expiratory
◦ UMN passing to contralteral expiratory muscles
* Nucleus para-ambigualis
◦ Inspiratory
◦ Force of contraction of contralteral inspiratory muscles
‣ Rostral ventral respiratory group
* Nucleus ambiguous
◦ Airway dilator functions of the larynx, pharynx and tongue
‣ Pre-Botzinger
* Central pattern generator is primarily located here but groups of neutrons are spread throughout the medulla
‣ Botzinger
* Within the nucleus retrofacialis
* Expiratory functions
Other than the 2 medullary respiratory groups which other brainstem centre has some respiratory regulation? What does it do? Connections to where?
Pontine respiratory group
* Fine tuning the timing of respiration
* Connections to the hypothalamus, cortex and nucleus tractus solitaris
* Apneustic centre
◦ Lower pons
◦ Excitatory function - gasping respirations
* Pneumotaxic centre
◦ Can inhibit inspiration - fine control of frequency
What two subcomponents to the pontine respiratory group are there? What are their functions?
Pontine respiratory group
* Fine tuning the timing of respiration
* Connections to the hypothalamus, cortex and nucleus tractus solitaris
* Apneustic centre
◦ Lower pons
◦ Excitatory function - gasping respirations
* Pneumotaxic centre
◦ Can inhibit inspiration - fine control of frequency
What 3 regulatory centres factor inot medullary central pattern generator? What 2 other feedback factors are there?
Pons
Hypothalamus
Cortex
Non respiraotry reflexes
Chemoreceptors, mechanorecpeotrs
What are the effectors of respiration? Where do they get their nerve suppply?
- Diaphragm - phenric nerve
◦ Phrenic nerve input - ramp pattern input only, as expiration is passive at baseline - Intercostal muscles
◦ External intercostal muscles - inspiration
◦ Internal intercostal muscles - expiration
◦ Transverse - Abdominal muscles - active
- Accessory muscles - SCM, scalenes
What is the ventilatory response to icnreasing PCO2
Increasing ventilation linearly
for every 1mmHg rise –> 2L/min MV increase
How is increasing PCO2 sensed?
Peripheral chemoreceptors over seconds –> 20% of response
Central chemoreceptors over minutes
How is increased minute ventilation in response to increased PCO2 achieved
Both increased RR and TV
Draw a CO2 response curve
Using a CO2 response curve describe how hypoxia changes it?
‣ Metabolic acidosis and hypoxia shift the CO2/ventilation response curve to the left
‣ Sleep, sedation and anaesthesia shift it to the right and decrease the slope (i.e. increase in minute ventilation is reduced per unit of rise in CO2.
‣ Age reduces the response also.
‣ Higher levels of physical fitness also diminish the drive.
‣ PaCO2 is fairly linear in the range 45-80 mmHg
Over what range does PCO2 response with increased ventilation occur linearly
45 - 80mmHg
What factors shift a CO2 response curve to the left? What does this imply?
Hypoxia
Metabolic acidosis
Implies increased responsiveness to CO2
What factors shift a CO2 response curve to the right?
‣ Metabolic acidosis and hypoxia shift the CO2/ventilation response curve to the left
‣ Sleep, sedation and anaesthesia shift it to the right and decrease the slope (i.e. increase in minute ventilation is reduced per unit of rise in CO2.
‣ Age reduces the response also.
‣ Higher levels of physical fitness also diminish the drive.
‣ PaCO2 is fairly linear in the range 45-80 mmHg
How do sleep and sedation influence the CO2 response curve?
‣ Metabolic acidosis and hypoxia shift the CO2/ventilation response curve to the left
‣ Sleep, sedation and anaesthesia shift it to the right and decrease the slope (i.e. increase in minute ventilation is reduced per unit of rise in CO2.
‣ Age reduces the response also.
‣ Higher levels of physical fitness also diminish the drive.
‣ PaCO2 is fairly linear in the range 45-80 mmHg
What factors other than oxygen, acidosis and sedation influence the CO2 response curve? 5
‣ Age reduces the response also.
‣ Higher levels of physical fitness also diminish the drive.
- Genetics/interindividual variation
- CO2 retnetion with COPD, OSA, OHS have blunted response
- Hypothyroidism
- Metabolic Alkalosis
Which is the maximum ventilatory response to increased PCO2
At 100mmHg respiratory fatigue adn narcosis develop
What is the pattern of ventilatory response to PCO2 over time?
‣ 15-30% of response within 1 minute (peripheral)
‣ Response 75% of maximal minute volume change over 2-3 minutes (central)
‣ Remains ~15-25% change is over hours via unknown mechanism
With prolonged CO2 retention what occurs?
‣ Choroidal active secretion fo bicrbaonte into CSF normalising pH and reducing and ceasing central chemoreceptor stimulation
‣ Additionally systemic pH normalised with renal retention of bicarbonate again reducing response at carotid bodies
What is the primary controller of ventilation?
CO2
How to measure PCO2 vs ventilation response
◦ Rebreathing from a bag - use ABG to monitor PCO2 and alveolar CO2 extrapolate form this
◦ Inspiratory ressure following brief occlusion
How does sleep affect CO2
Baseline increase in 1-2mmHg at most due to reduced responsiveness (right shift of the CO2 response curve)
How does work of breathing affect CO2 response curves?
ventilation is less affected by increasing PCO2 if already high levels of work of breathing
Draw a graph representing PCO2 for minute ventilation?
Draw a CO2 response curve representing the changing effects of PaO2, sleep, opiates, anaesthesia, metabolic acidosis?
How would you describe the oxygen relationship?
Synergistic
How does PaO2 affect ventilation
- Synergistic effect on PCO2 - if PCO2 elevated then changes in oxygenation will prompt increased ventilatory response, increased gradient of curve, with the same X axis intercept for PaCO2 having no ventilatory drive
- PaO2 response curve once alveolar PaOP2 dropping to 50mmHg
How does PaO2 affect ventilation when PaCO2 normal
Only if PaO2 drops <60mmHg
Does PaO2 have any effect on ventilation at a PaO2 of 80mmHg
Minimal unless there is additionally a rise in PaCO2 and then there is an increased response compared to a PaO2 of 100mmHg with a similar PaCO2
Where does the PaO2 response come from
◦ This response comes entirely from the chemoreceptors peripherally - takes seconds to respond. No central chemoreceptor effect. Receptors sense oxygen tension rather than content i.e. not triggered by anaemia
Draw a PaO2 response curve. Include the effect of PaCO2 on the PaO2 response curve
Why is it harder to measure PaO2 response curves
Notably this is partly because as you increase your ventilation you affect PaCO2 and subsequent respiratory drive from this. The response is stronger if you control for CO2 and maintain it as constant but this is not representative of physiological circumstances that are likely to be encountered.
What change is seen with changing PaO2 from 100 –> 40mmHg (sats 60%)
3x increase in ventilation
Maximum minute ventilation occurs at
120-140L/min
Complete respiraotry collapse occurs at what PaO2
13mmHg
What changes the ventilatory response to hypoxia
Gas (2)
Sensory (2)
Patient (2)
Gas (2)
Sensory (2)
Patient (2)
- Hypocapnoea
- Carotid endarterectomy - sensory glomus destroyed
- CNS depression - sleep, anaesthesia, opiates
◦ Sleep response 1/3 of the strength - For the record, one should increase one’s minute volume by roughly 1L per every 1% drop in arterial saturation. - Starvation - decreases by 40%
- Age - desensitisation by 70 such that drive is 50% of previous
- Chronic hypoxia
◦ altitude exposure
◦ Chronic exposure to high oxygen demand - endurance athletes
◦ Disease
What 2 factors increase the ventilatory response to hypoxia
Hypercapnoea
exercise
What pattern does the ventilatory response to hypoxia show
- Acute phase - minute volume increases abruptly over 5-10 minutes
- Decline phase - minute volume decreases to a higher baseline plateau - breathing at a slightly higher rate maintaing a lower baseline PaCO2
- If isocapnoeic there is a third phase where minute volume rises again gradually over many hours
◦ Only seen when stable CO2 is maintained despite hypoxia
◦ Plateaus at 24 hours
How do you test the oxygen response curve
Breathe through a closed circuit spirometer with dropping FiO2 and a CO2 scrubber in the expiratory limb
How do you test CO2 response cruves
Rebreathign CO2 testing sensor response
How do you test central respiratory drive an its effectors
100 milisecond occlusion and tests pressure generated by inspiratory muscles as a surrogate for central respiratory drive
Describe the cardiovascular response to hypoxia
- Hypoxic vasoconstriction in the pulmonary circulation and vasodilatation in the systemic circulation
- Increased hydrogen ion levels shift the HbO2 curve right enabling improved O2 delivery at the tissues
- Eventually the brain becomes hypoxaemic and respiratory drive is depressed, thereby removing respiratory compensation and resulting in increasing acidosis, failure of the Na.K.ATPase pumps in most cells, cell lysis and death.
- Increased sympathetic and vagal tone, but the sympathetic increase dominates
- Increased cardiac output and tachycardia are the net result
- Hypoxic systemic vasodilation prevents hypertension
How does hypoxia affect at a cellular level
Cellular At a tissue mitochondrial level
* When the partial pressure reaching the mitochondria drops below 5mmHg
* Oxidative phosphorylation is impaired
* Anaerobic pathways of glucose metabolism of energy production utilised producing lactate and hydrogen ions
* Cause an increased anion gap metabolic acidosis due to lactate (pH < 7.35)
How does hypoxia affect acid base?
Acid-Base Changes
* Hypoxia results in both fixed and volatile acid-base disturbances
* Anaerobic metabolism results in lactate production
* Production of fixed acid results in a base deficit, and a low bicarbonate
* Hypoxia and metabolic acidosis stimulate ventilation and hypocarbia
If you were to describe the body response to hypoxia how would you divide it?
Acute ventilatory changes
Cardiovascular
Cell based
Acid base
Chronic adaptive
Chronic hypoxia response
- Specialized interstitial cells in the inner cortex and outer medulla of the kidney respond to hypoxia by producing and secreting EPO - Increasing Red Blood Cells and Hemoglobin Concentration
◦ Hypoxia inducible factors which mediate the effects of hypoxia
◦ causes Increased angiogenesis
* will also lead to cerebral acidosis (via anaerobic metabolism), which will stimulate central pH receptors and stimulate ventilation
What is alveolar ventilation
the volume of gas participating in gas exchange
Measured alveolar ventilation = respiratory rate x (tidal volume - dead space)
What is the alveolar ventilatino equation
Measured alveolar ventilation = respiratory rate x (tidal volume - dead space)
What are the factors whihc influence respiratory rate adn volume
PaO2
PaCO2
pH
Temperature
Exercise
Cardiac output/BP
How does pH affect respiratory drive?
- Sensed Centrally
◦ Decreased pH in the CSF increases the respiratory rate and tidal volume
◦ (slow acting, steady state control; adjustments occur over minutes) - Effect - increased minute ventilation which ameliorates the acidosis, and drops PaCO2 which then drops the respiratory drive
- Linear effect over survivable pH range
How is temperature sensed and how does it affect ventilation
- Increased sensitivity of periphperal chemoreceptors to O2 and CO2 with increased body temperature
◦ Increased sensitivity of central chemoreceptors to changes in pH - A rise in temperature will increase the minute volume at any given PaCO2 and PaO2 level
- Responses to hypoxia and hypercapnia are
- amplified by hyperthermia
