Theme 3: Respiratory Physiology Flashcards
What is the difference between PaO2 and PAO2?
- PaO2 -> In arterial blood
- PAO2 -> In alveoli
Draw a graph of how PAO2 and PACO2 change with ventilation.
What is a simple indicator of hyperventilation?
- A low PACO2
- This is because hyperventilation is one of the only causes of a low PACO2 (although a high PACO2 has many causes)
Write out the alveolar gas equation.
PAO2 = PIO2 - (PaCO2/0.8)
(The alveolar gas equation is used to estimate the partial pressure of oxygen in the alveoli using parameters that are easier to measure. A more complicated version is in the picture.)
What important measure does ABG analysis allow to be calculated?
- It enables the A-a (Alveolar-arterial) PO2 gradient to be calculated
- This is because the arterial PO2 is directly measured, while the alveolar PO2 can be estimated using the alveolar gas equation
- If there is a high A-a gradient, this suggests that there is a problem with gas exchange
Summarise the two types of respiratory failure.
- Type 1 respiratory failure -> Gas exchange failure
- Type 2 respiratory failure -> Ventilatory failure
Draw a graph to explain type 2 respiratory failure.
- Type 2 respiratory failure is ventilatory failure, where the lungs do not ventilate hard enough
- This means that PaO2 is low (less than 8kPa), while PaCO2 is high (more than 6kPa)
- The A-a gradient remains small, since there is no problem with gas exchange in the lungs
What are some ways in which type 2 respiratory failure may be treated?
- Naloxone (opiate antagonist) -> This is because opiates can cause ventilatory failure
- Non-invasive ventilation (NIV)
- Invasive mechanical ventilation
Draw a graph to explain type 1 respiratory failure.
- Type 1 respiratory failure is gas exchange failure -> Ventilation is increased, if anything
- This means that PaO2 is low (less than 8kPa) AND PaCO2 is also low (less than 6kPa)
- The A-a PO2 gradient is greatly increased, but CO2 is less affected
Name some conditions that can feature type 1 respiratory failure.
- Asthma
- COPD
- Pulmonary fibrosis
- Acute respiratory distress syndrome (ARDS)
Describe the epidemiology, pathophysiology, diagnosis and treatment of asthma.
- Affects over 2 million children and 3 million adults in UK, leading to chronic airway inflammation (bronchitis and bronchiolitis) and acute ‘attacks’.
- Airway obstruction is related to inflammatory cell infiltration, mucus secretion and bronchoconstriction
- Airway remodelling occurs due to thickened basement membrane, smooth muscle hypertrophy and hyperplasia
- Diagnosis is done via a peak flow meter and measurement of FEV1
- Treatment usually involves steroid or bronchodilator inhalers
Give experimental evidence for how type 1 respiratory failure occurs in asthma.
(McFadden, 1968):
- Performed ABG analysis in patients during an asthma attack
- Plotted arterial PO2 against percentage of the predicted FEV1 achieved by the patient -> Found that there was a linear relationship where decreased FEV1 led to lower arterial PO2
- This would seem to suggest that the arterial PO2 falls due to hypoventilation
- However, the same study showed that asthma is normally associated with alveolar hyperventilation
- Only very few patients were found to have high PaCO2, which is associated with very low FEV1
- Instead, respiratory failure in asthma is thought to be due to V/Q mismatch (and PaCO2 is high)
Is V/Q mismatch compensated in terms of oxygen and carbon dioxide?
- The graphs of partial pressure of O2 or CO2 against O2 or CO2 concentration in the blood show that O2 concentration plateaus much earlier than the CO2
- This means that the area of high V/Q can compensate for the area of low V/Q in the case of carbon dioxide, but not oxygen
- Thus, in conditions such as asthma, the A-a gradient is increased for oxygen but not carbon dioxide
What is COPD?
COPD = Emphysema and chronic bronchitis
- (Usually) smoking-related airflow limitation due to chronic airway inflammation and alveolar wall destruction.
- It is not fully reversible.
Describe the three compartment model of V/Q mismatch.
- The model considers three extremes of V/Q mismatch:
- Shunt -> Where there is blood flow but no ventilation
- Normal alveolus
- Alveolar dead space -> Where there is ventilation but no blood flow
- Each of these corresponds to a different extreme on the graph of PCO2 against PO2
- Shunt leads to a V/Q ratio that is very low, a normal alveolus has a ratio of around 1, while alveolar dead space leads to a high V/Q ratio
How does V/Q ratio change throughout the lung?
- V/Q increases towards the top of the lung.
- This means that there is a range of V/Q’s throughout the lungs, so there is no actual “normal” alveolus
Describe a technique to quantify the distribution of V/Q ratios throughout the lungs.
MIGET:
- Infusion of a mixture of six inert gases* for 20-30 min
- Sample of mixed venous blood from a Swan Ganz catheter
- Sample of arterial blood (usually from the radial artery)
- Sample of mixed expired gas, plus measurement of total ventilation
The data is then plugged into a computer, which is asked to calculate the various V/Q ratios that best match the data, given that there are, for example, 50 areas of the lung. These areas are then plotted on a graph, as below, to show the distribution of V/Q ratios.
How does COPD appear on a MIGET reading?
- The left graph shows a more emphysema-like pheontype, where there are areas of almost dead space with high ventilation but no blood flow -> This leads to some high V/Q ratios
- The right graph shows a more bronchoconstrictive phenotype, where there are areas of almost shunt with high blood flow but no ventilation -> This leads to some low V/Q ratios
Is 100% oxygen infusion a good idea to combat COPD and asthma? Give experimental evidence.
(Ballester, 1989):
- Used MIGET to study V/Q distribution in the lungs
- Found that 100% oxygen supply led to worsening of the V/Q mismatch, since hypoxic pulmonary vasoconstriction is inhibited
What is pulmonary fibrosis and how does it lead to type 1 respiratory failure?
- It is a end-point of various diverse pathologies
- It involves loss of normal architecture and collagen deposition leading to pulmonary fibrosis
- This means that there is reduced rate of gas exchange and therefore diffusion limitation can happen
- This tends to be exacerbated during exercise
What is ARDS?
Acute respiratory distress syndrome:
- Involves tachypnoea, hypoxaemia and low lung compliance.
- Looks similar to the ‘hyaline membrane disease’ previously described in newborn infants (IRDS)
- Involves diffuse alveolar damage with many possible triggers, often not primary lung disease (e.g. sepsis).
- The alveolar damage can include:
- Inflammatory cell infiltrate and fluid accumulation
- Thickening of the blood-gas barrier
- Problems with the capillaries
What is the best treatment for ARDS and how is this optimised?
- Invasive mechanical ventilation
- This can be improved using PEEP (positive end-expiratory pressure), which prevents alveolar collapse, which can otherwise causes loss of lung compliance and significant shunt.
Does shunt improve with oxygen therapy?
No
What are the two main types of pressure in the lungs?
- Intrapulmonary pressure
- Intrapleural pressure
What pressure keeps the lungs open?
- Transpulmonary pressure
- This is the difference between the intrapulmonary and intrapleural pressures
- It can be altered in pneumothorax, pleural effusion, asthma or COPD
Draw a graph to show how intrapleural, intrapulmonary and trans-pulmonary pressures change during the ventilation cycle.
What are the two main variables to consider in invasive ventilation (positive pressure ventilation)?
- Resistance
- Compliance
How is compliance relevant to invasive ventilation?
- The alveoli are least compliant at very low and very high volumes
- This means that we must aim to maintain the pressure in an intermediate range where compliance is high
- Otherwise, if the volume is too small, the alveoli may collapse and if the volume is too large, there is risk of trauma
How is resistance relevant to invasive ventilation?
It is a key determinant of flow.
Write an equation for flow during invasive ventilation.
This means that flow through the endotracheal tube can be increased by:
- Increased radius
- Decreased length
- Increased pressure gradient
What are some conditions that can involve reduced lung compliance?
- Pulmonary oedema
- Pneumonia
- Pulmonary fibrosis
- Premature birth
What is PEEP? Give details.
Positive end-expiratory pressure (PEEP):
- This is the low level of positive pressure at the end of expiration during invasive ventilation
- It is used to prevent collapse of alveoli
- It also increases functional residual capacity (FRC) and improves oxygenation
- Usually set to 5 cm H2O, but can be increased to 20 cm H2O in severe respiratory failure
What is total inspiratory pressure?
It is the total pressure required to deliver a desired volume in invasive ventilation.
What is plateau pressure?
- The pressure when there is no airflow during invasive ventilation -> This is when inspiration is complete
- It is determined by compliance
- If there is a problem with compliance, plateau pressure will rise
What is mean alveolar pressure?
- It is the average pressure in the alveoli during the respiratory cycle
- The higher the MAP, the more alveoli are open for gas exchange
How can mean alveolar pressure be increased?
- Increasing inspiratory pressure
- Increasing time spent in inspiration
- Increasing the PEEP
What are the indications for invasive ventilation?
ABCDE
- Airway – Airway protection (e.g. head injury, low GCS)
- Breathing – Reduction in work of breathing, acute respiratory failure
- Circulation – Optimise oxygen delivery and minimise consumption
- Disability – Reduced consciousness (status epilepticus, meningitis)
- Everything else – Surgery, procedures, transport
What are the main benefits of invasive ventilation?
- Improve oxygenation
- Clearance of carbon dioxide
- Reduced work of breathing
What are some consequences of invasive ventilation?
- Complications related to tracheal intubation
- Airway & dental trauma
- Laryngeal dysfunction, tracheal stenosis, tracheomalacia
- Airway obstruction
- Haemodynamic instability
- Increased shunt
- Ventilation of poorly perfused lung
- Increased dead space
- Ventilator-associated pneumonia (≈1% per day)
- Oxygen toxicity (FiO2 > 0.6)
- Ventilator-associated lung injury
What is the problem with spending too long in inspiration?
It can lead to CO2 retention.
What are the different forms of ventilator-associated lung injury?
- Barotrauma - high airway pressures
- Volutrauma - alveolar over-distension
- Atelectatrauma - repetitive alveolar collapse & reopening
- Biotrauma
- Pro & anti-inflammatory cytokines
- Pulmonary inflammatory response
- Loss of alveolar compartmentalisation
- Systemic inflammation and multi-organ failure
Give some experimental evidence for how invasive ventilation can be optimised.
(ARMA study, 2000):
- Compared ventilation with low tidal volumes to more traditionally-used high tidal volumes in treatment of ARDS
- Found that this lead to lower death rates
- This is because high tidal volumes led to barotraumas
- This influenced a lot of future understanding of ventilation management
Describe the parameters of lung-protective invasive ventilation.
- Maintenance of plateau pressure < 30 cmH2O
- Tidal volumes ≤ 6 ml/kg
- Application of PEEP to reduce alveolar opening-collapse
What are the two main modes of invasive ventilation?
- Pressure control (pressure generator)
- Flow/volume control (flow generator)
Note: Volume and flow are interchangeable (as V = Q x t).
Describe volume controlled ventilation.
- Preset tidal volume is delivered
- Pressure required will depend on compliance and resistance
- No leak compensation (leak = loss of tidal volume)
- Avoids volutrauma – can be set to 6 mls/kg
- Useful in theatre, ICU, ARDS
In other words, volume controlled ventilation involves delivering a given volume using whatever pressure is required.
Describe pressure controlled ventilation.
- Delivers set pressure during inspiration
- Tidal volume generated is variable and therefore runs the risk of generating a tidal volume that is too low (e.g. when the resistance is high)
- Compensates for leaks (non-invasive use)
- Avoids barotrauma
- Useful in ICU, paeds, non-invasive, trauma
How can oxygenation during invasive ventilation be improved?
It is all dependent on mitigating the effect of shunt:
- Increasing FiO2 – ceiling effect once shunt fraction is 30%
- Re-opening closed alveoli (recruitment)
- Increase time spent in inspiration
How can the CO2 be effectively cleared during invasive ventilation?
- Increase alveolar minute ventilation
- Permissive hypercapnia may be required
Where are the peripheral and central chemoreceptors?
- Peripheral chemoreceptors -> Carotid bodies (at the bifurcation of the common carotid artery)
- Central chemoreceptors -> In the brainstem
Describe the innervation of the carotid body.
- Innervated by the carotid sinus nerve
- These nerves originate in the petrosal ganglia and project back to the NTS in the brainstem
What does the carotid body sense?
- It is mostly responsive to oxygen
- But it is also sensitive to CO2 and pH to a lesser extent
Describe the structure of the carotid bodies.
- Type 1 cells
- Neuroectodermal origin
- Responsible for oxygen-sensing
- Contain neurotransmitters and make contact with carotid sinus nerve
- Type 2 cells
- Exact function not known
- Probably play a role in neuromodulation and maintaining local environment
Give some experimental evidence for the role of type 1 cells in the carotid body.
(Zhang, 2000):
- Co-cultured type 1 cells with petrosal ganglion cells
- Only the neurons that connected to the type 1 cells became chemosensitive
- The response to hypoxia was completely abolished by a combination of hexamethonium (ACh blocker) and suramin (P2X blocker)
- This showed the importance of these neurotransmitters
Give some experimental evidence for the importance of ATP transmission in the carotid body.
(Rong, 2003):
- Performed knockout of P2X receptors in mice
- This led to diminished ventilatory response to hypoxia
- This shows the importance of ATP transmission between type 1 cells in the carotid body and petrosal ganglion cells
Give some experimental evidence for how chemoreception in the carotid body leads to neurotransmitter release.
(Buckler, 1994) [OXYGEN]:
- Removed extracellular calcium and added 1mM of EGTA to type 1 carotid body cells
- This led to almost complete attenuation of the response to anoxia, showing the importance of calcium in chemotransduction
- Voltage-clamping of the cell led to a slower and more attenuated increase in calcium in response to anoxia
- This shows the importance of extracellular calcium influx in chemotransduction
(Buckler, 1994) [CO2]:
- Voltage-clamping of type 1 carotid body cells led to attentuation of the intracellular calcium increase in response to hypercapnia
What leads to calcium influx during hypoxia in type 1 carotid body cells? Give experimental evidence.
- Closing of potassium channels
- (Buckler, 1997):
- Used a voltage-clamp set-up with a ramp protocol in which the voltage is oscillated between -30 and -90mV
- Induced a period of anoxia within the protocol
- Plotted an I/V graph under control and anoxic conditions
- Subtracting the two curves gives the I/V relationship for whatever channels are responsible for this difference (“Oxygen-sensitive currents were determined by subtracting the I/V relation obtained under hypoxic conditions from that obtained under control conditions”)
- The reversal potential of this current is around -90mV, which indicates that the change is caused by the closing of potassium channels during anoxia -> This leads to depolarisation and opening of VGCCs
- (Buckler, 2000):
- Utilised a similar ramp protocol to the one above
- Plotted an I/V graph under control and pH 6.4 conditions
- Subtracting the two curves gives the I/V relationship for whatever channels are responsible for this difference
- The reversal potential of this current is around -90mV, which indicates that the change is caused by the closing of potassium channels during -> This leads to depolarisation and opening of VGCCs
- A high potassium extracellular environment leads to a shift of the I/V curve to more depolarised voltages, indicating that the current is definitely potassium-dependent
What leads to calcium influx during acidosis in type 1 carotid body cells? Give experimental evidence.
(Buckler, 2000):
- Used a voltage-clamp set-up with a ramp protocol in which the voltage is oscillated between voltages
- Plotted an I/V graph under control and pH 6.4 conditions
- Subtracting the two curves gives the I/V relationship for whatever channels are responsible for this difference
- The reversal potential of this current is around -90mV, which indicates that the change is caused by the closing of potassium channels during -> This leads to depolarisation and opening of VGCCs
- A high potassium extracellular environment leads to a shift of the I/V curve to more depolarised voltages, indicating that the current is definitely potassium-dependent
Describe H2S metabolism and how it is related to oxygen sensing.
- H2S metabolism is suggested to be affected by possible different pathways:
- There is an oxygen-sensitive pathway that affects the activity of γ-cystathionase (a.k.a. cystathionine γ-lyase) -> This reduces the formation of H2S
- H2S degradation is linked to the electron transport chain, making complex IV the effective oxygen sensor
Describe the heme-oxygenase-2 sensor model of oxygen sensing in the carotid body. Give experimental evidence for whether this is valid.
- During hypoxia:
- Lack of oxygen inhibits heme-oxygenase-2 (the oxygen sensor)
- This leads to less CO production
- This leads to less activation of guanylate cyclase and PKG
- This leads to increased activity of cystathionine γ-lyase
- Finally, H2S production is increased
- This leads to increased carotid body activity by a debated mechanism
- However, the mechanism has largely been disproved.
- (Ortega-Saenz, 2006):
- Measured neurosecretion from carotid body cells as a measure of carotid body activity
- Compared wild-type and heme-oxygenase-2 knockout mice
- There was no significant difference between the activity in the wild-type and knockout mice
- Hence, this argues against the idea that heme-oxygenase-2 is an oxygen sensor
Give experimental evidence for and against the role of the mitochondria in oxygen sensing in the carotid body.
FOR
- Inhibitors of oxidative phosphorylation (e.g. DNP and cyanide) depolarise type 1 cells -> This response is blunted by voltage clamping
- (Wyatt, 2004):
- Plotted the I/V relationship for control, hypoxia and with the addition of mitochondrial inhibitors (rotenone, NaCN, FCCP)
- The I/V relationship with each of the drugs was unaffected by the presence of hypoxia
- This suggests that complete inhibition of mitochondrial activity mimics the effects of hypoxia on the background potassium current
AGAINST
- It can be argued that the mitochondria are only sensitive enough to detect very severe hypoxia (below around 0.2 Torr), which is not comparable to the hypoxia seen in arterial blood that triggers increased carotid body firing -> However, the oxgen content of blood in the capillaries is much lower, so this could help explain things partly
- (Lahiri, 1993):
- Plotted carotid body impulses per second against PO2 in arterial blood and microvasculature
- Both showed that the lower the PO2, the more rapidly the carotid body fires
- However, even the more left-shifted microvasculature curve could not be explained by the low sensitivity of mitochondrial metabolism to oxygen
FOR
- However, mitochondria could still completely explain oxygen sensing in the carotid body if they had higher sensitivity in type 1 cells in particular
- (Biscoe, 1992):
- Used rhodamine 123 as a dye to measure mitochondrial fucntion in carotid body cells
- Found that oxygen sensitivity was higher than previously thought, more closely matching the profile shown by the carotid body to oxygen
- (Buckler, 2013):
- Plotted a graph of NADH fluorescence (NADH is fluorescent itself) against PO2 for a sympathetic neuron and carotid body type 1 cell
- The type 1 cell’s mitochondria showed much higher sensitivity to hypoxia than the sympathetic neuron’s mitochondria
- Also exposed type 1 cells to a cocktail of rotenone, antimycin A, myxothiazol and oligomycin to block complexes I, III and V.
- This depolarised the mitochondrial membrane, after which FCCP was added and the fact it had no further effect on the Rh123 signal suggested that mitochondria are fully depolarised and electron transport is fully inhibited.
- TMPD and ascorbate were added to provide a source of electrons to cytochrome c and thus substrate for cytochrome oxidase -> This led to fast repolarisation of the mitochondrial membrane.
- Now the activity of cytochrome oxidase in response to hypoxia could be tested by controlling the oxygen content.
- Progressively more severe hypoxia led to increased Rh123 fluorescence, with anoxia leading to almost maximal fluorescence compared to before TMPD and ascorbate were added.
- The same results were not seen in superior cervical ganglion cells.
- This demonstrates the importance of cytochrome oxidase in oxygen sensing in thre mitochondria.
- Transcriptomic studies in mice reveal atypical and novel cytochrome oxidase subunits that are differentially expressed (up regulated) in the carotid body compared to sympathetic neurones/chromaffin cells.
- Overall, these do show that mitochondria could plausibly be the oxygen sensor in the carotid body
Give some experimental evidence for the role of ROS generation by complex 1 in linking mitochondria and membrane ion channels in oxygen sensing in carotid body cells. Describe the model.
FOR
- (Fernández-Agüera, 2015):
- Produced a knockout of one of the subunits of complex 1 -> This was a targeted KO (not whole body, or it would be lethal)
- This led to abolishing of the response to hypoxia but not to CO2
- This suggests that oxidative phosphorylation plays an important role in oxygen sensing, BUT it does not prove that there is anything special about complex 1 in this process
- Showed that H2O2 (produced during hypoxia) led to closing of background potassium channels
- The model:
- During hypoxia, the ETC becomes backed up
- This leads to production of ROS and NADH at complexes 1 and 3
- The ROS signal to membrane channels
AGAINST
- (Find reference):
- Exposed a carotid body cell to increasing degrees of hypoxia
- This led to progressively larger increases in intracellular calcium
- However, when exposed to hypoxia, there was still a very large increase in intracellular calcium
- This suggests that ROS cannot be playing a role since ROS cannot be produced when there is no oxygen at all
- (Find reference):
- Measured the increase in intracellular calcium in type 1 cells driven by rotenone (complex I inhibitor)
- This would seem to support the importance of ROS generation by complex 1 in oxygen sensing, but the effect could be blocked by TMPD/ascorbate (electron donor)
- The TMPD/ascorbate acts by facilitating cytochrome oxidase, which shows that complex 1 is not essential in oxygen sensing
What are the main neural phases of normal ventilation?
- Expiration
- Inspiration
- Post-inspiratory / Early expiratory phase -> This is a short burst of activity seen mostly in the phrenic nerve
What are the different types ofrespiratory-related neurons in the ventral respiratory group?
- Inspiratory ramp neurons -> Firing increases gradually during inspiration
- Early-inspiratory neurons -> Firing is highest at the start of inspiration, then gradually reduces
- Post-inspiratory neurons -> Firing is highest just after inspiration and then gradually reduces
- Expiratory ramp neurons -> Firing increases gradually during expiration
Describe the conditional network bursting theory three phase model of ventilatory control.
- The network involves three main types of interconnected cells: early-insiratory neurons, post-inspiratory neurons and expiratory neurons
- Each of these three exerts inhibitory control over the other two
- Output from the network is via the bulbospinal neuron, which outputs via the phrenic nerve -> The bulbospinal neuron is inhibited by the post-inspiratory and expiratory neurons, but excited by the inspiratory ramp neurons
Phase 1 (inspiration):
- The early-inspiratory neurons start the cycle and decrease in firing over time since they are adaptive neurons.
- The early-inspiratory neurons lead to inhibition of the post-inspiratory neurons and expiratory neurons, so there is no inhibition of the bulbospinal neurons.
- Instead, the inspiratory ramp neurons excite the bulbospinal neurons, leading to phrenic nerve activity.
Phase 2 (post-inspiration):
- The early-inspiratory neurons eventually finish firing since they are adaptive.
- This releases inhibition from the post-inspiratory neurons (and expiratory neurons).
- The post-inspiratory neurons inhibit all the other neurons, including the bulbospinal neurons, leading to reduced phrenic nerve activity.
Phase 3 (expiration):
- The post-inspiratory neurons are adaptive so they eventually finish firing and release inhibition from the excitatory ramp neurons.
- These then inhibit all the other neurons, including the bulbospinal neurons, leading to reduced phrenic nerve activity.
- Since the expiratory neurons are ramping, there must be an off switch that enables phase 1 to begin again.
- This comes from pre-inspiratory neurons that become active just before inspiration and inhibit the excitatory ramp neurons.
- This releases inhibition from the inspiratory ramp neurons, so phase 1 can begin again.
Draw phase 1 of the conditional network bursting theory three phase model of ventilatory control.
Draw phase 2 of the conditional network bursting theory three phase model of ventilatory control.
Draw phase 3 of the conditional network bursting theory three phase model of ventilatory control.
Note that there should also be pre-inspiratory neurons on this diagram that inhibit E2 and hence end phase 3.
Describe a pacemaker model for ventilatory control. Give experimental evidence.
(Smith, 1991):
- Performed serial sectioning of the brainstem (gradually removing slices of the brainstem starting from the pons)
- Ventilatory rhythm was conserved until the pre-Botzinger complex was reached
- The Botzinger complex itself (just rostral to the pre-Botzinger complex) appears to not be essential for rhythm generation despite being the main location for post-inspiratory neurons
(Onimaru, 2003):
- Used a voltage-sensitive dye (Di-2-ANEPEQ) to image spatiotemporal pattern of respiratory neuron activity
- The first signs of activity were seen 200ms before the start of inspiration (as defined by the first activity in the phrenic nerve)
- The researchers decided that this activity was not pre-inspiratory but late expiratory
- This led to the idea that there are two pacemakers:
- Pre-inspiratory pacemaker -> Pre-Botzinger complex
- Late expiratory pacemaker -> Parafacial respiratory group
- However, this late expiratory pacemaker seems to only be observed during forced expiration
Give experimental evidence for a hybrid model of ventilatory control.
(Dutschmann, 2003):
- Performed serial sectioning of the brainstem (gradually removing slices of the brainstem starting from the pons) in a in situ neonatal rat preparation
- Intact preparation:
- Showed signs of post-inspiratory activity in the cervical vagus nerve
- The hypoglossal nerve activity starts just before the post-inspiratory activity in the vagus nerve and activity in the phrenic nerve -> This enables the airways to open before inspiration
- All three nerves show ramping activity
- Medullary preparation (i.e. medulla intact):
- Showed lack of post-inspiratory activity (so only have 2 phase ventilation, not 3)
- Bursts synchronised in all three nerves
- The waves of activity in each nerve lose their ramping, leading to square wave bursts
- Pre-Botzinger complex preparation (i.e. pBC intact):
- The waves of activity now have a decrementing shape (opposite to ramping) -> More like gasping
- This suggests a hierarchy of oscillators -> Some evidence for this is that the pre-Botzinger complex neurons have sodium currents involved in rhythm generation, which can be blocked by riluzole. Riluzole blocks rhythm generation in the pre-Botzinger complex preparation, but not the intact preparation, which suggests a hierarchal model.
Draw a hybrid model of ventilatory control.
- There is still a core oscillator network in the medulla:
- Botzinger complex -> Contains post-inspiratory and augmenting expiratory neurons, which are inhibitory
- Pre-Botzinger complex -> Contains pre-inspiratory (excitatory) and early-inspiratory neurons
- The pre-inspiratory neurons output via the inspiratory ramp neurons (in the rostral ventral respiratory group), which are also excitatory -> This is the main output path to phrenic nerve
- The pre-inspiratory neurons also output to the hypoglossal nucleus (not shown) and thus control the upper airways
- Late expiratory neurons:
- Late expiratory neurons (in the parafacial respiratory group) provide excitatory output to the caudal ventral respiratory group, which excite muscles of expiration
- Late expiratory neurons also provide excitatory output to the augmenting expiratory neurons to prolong the expiratory phase
- Post-inspiratory neurons and early inspiratory neurons also inhibit the late expiratory neurons, which ensures that there is no expiration during expiration
- Tonic drive comes from the pons
Describe an alternative hybrid model of ventilatory control.
- (Anderson, 2017):
- Propose a Triple Oscillator hypothesis of ventilatory control
- This is due to the discovery of the PiCo nucleus
- This means that each of the three main inhibitory neuron types in the inhibitory ring has its own personal pacemaker:
- Expiratory neurons -> Have the parafacial respiratory group neurons
- Early inspiratory neurons -> Have the pre-inspiratory neurons in the pre-Botzinger complex
- Post-inspiratory neurons -> Have the PiCo nucleus
- In resting states, ventilation is proposed to be two phase, with an inspiratory phase driven by the pre-Botzinger complex and a post-inspiratory phase driven by the PiCo nucleus
- In high metabolic states, ventilation is proposed to be three phase, with an addition active expiratory phase driven by the parafacial respiratory group neurons
What do central chemoreceptors detect?
Give a summary of control of breathing.
Describe the cycle of obstructive sleep apnoea.
Give experimental evidence for the mechanism of obstructive sleep apnoea.
(Eckert, 2013):
- Used a mask to vary upper airway pressures and induce expansion or collapse of the airway
- A period of airway collapse (induced by the mask) led to increasingly negative fluctuations in epiglottic pressure and increasingly positive genioglossus muscle activity (this is the muscle that tries to hold the airway open)
- The period of airway collapse also featured reduced airflow
- Eventually, the participant wakes up
What is the arousal stimulus to waking up in obstructive sleep apnoea?
- The subjects woke at a particular inspiratory effort, regardless of the cause of that increase in effort (whether it is hypoxia, hypercapnia or resistive load).
- Thus, in most, it is the increased inspiratory effort that awakes the patient with an obstructed upper airway.
How can we measure airway collapsability?
- Apply a pressure to the airway and plot it against airflow
- The pressure at which the airway collapses is called Pcrit
- Pcrit is higher in individuals with obstructive sleep apnoea
Compare Pcrit in individuals with obstructive sleep apnoea and healthy controls.
(Eckert, 2013):
- Plotted Pcrit against apnea-hypopnoea index (events per hour) for both healthy and OSA individuals
- The results showed that most patients with OSA have more collapsible airways (Pcrit above 2cmH2O) and healthy controls have less collapsible airways (Pcrit below 0cmH2O)
- However, there was overlap and significant variability within the 0-2cmH2O Pcrit range
Describe how arousal threshold varies in healthy and obstructive sleep apnoea patients.
(Eckert, 2013):
- Compared the arousal threshold (in terms of airway pressure in cmH2O) for healthy and OSA patients
- Healthy individuals on average wake up at relatively smaller respiratory efforts.
- Obstructive sleep apnoea patients on average do not wake up until there is a large effort to breath.
- There is a wide variability in both healthy individuals and OSA patients.
- Relatively ease of arousal at low respiratory efforts in some OSA patients contributes to the pathophysiology of their OSA -> This is because trivial obstructive events in non-REM sleep will wake the individual up so they do not get into REM sleep, where ventilation is more stable
Why do some obese individuals not have OSA? Give experimental evidence.
(Sands, 2014):
- Compared healthy controls with obese patients with and without obstructive sleep apnoea
- Compared the upper airway muscle responsiveness (pharyngeal dilator muscles) during an induced hypopnoea
- Overweight controls with no OSA showed on average increased muscle responsiveness when compared to the other two groups.
- This suggests that increased muscle responsiveness protects individuals from developing OSA.
What is loop gain and how can it be measured?
- Loop gain is a measure of ventilatory stability.
- It is measured experimentally by inducing a hypopnoea from holding CPAP setting.
- The hypopnoea is ended by returning the CPAP setting to a holding pressure.
- The reduction in ventilation during the hypopnoea (following compensation) is then compared to the overshoot in ventilation at the end of the hypopnoea.
- The ratio of the response to the initial disturbance is the loop gain.
Is a low loop gain or high loop gain better?
- This is a schematic of the ventilatory response to a hypopnoea in an individual with low loop gain (top) and a high loop gain (bottom).
- With low loop gain (top) following the hypopnoea there is hyperventilation followed by hypoventilation but this quickly settles and ventilation is quickly stabilised.
- With high loop gain following hypopnoea the cycles of hyperventilation and hypoventilation persist and the ventilatory system is unstable.
- High loop gain can precipitate instability and ongoing obstructive sleep apnoea.
Why might central sleep apnoea occur at altitude?
- At altitude, hyperventilation occurs to maintain pO2, which in turn leads to reduced pCO2
- When you sleep, the pCO2 is below the apnoeic threshold, so there is very low airflow
- This causes the pCO2 to creep up until the threshold is surpassed and there is a period of hyperventilation that reduces pCO2
Why might central sleep apnoea occur in congestive heart failure?
Significantly prolonged circulation times prolong the time to sensing the changes in carbon dioxide levels.
Summarise type 2 respiratory failure.
- Type 2 respiratory failure is ventilatory failure, where the lungs do not ventilate hard enough
- This means that PaO2 is low (less than 8kPa), while PaCO2 is high (more than 6kPa)
- The A-a gradient remains small, since there is no problem with gas exchange in the lungs
Draw a diagram to show the main causes of type 2 respiratory failure.
Describe a model that can be used to understand type 2 respiratory failure.
- In this model, if the capacity is greater than the load and there is sufficient drive, then there is adequate ventilation.
- If this changes, then type 2 respiratory failure may occur.
Describe an example of how reduced drive can lead to type 2 respiratory failure.
- Reduced ventilatory drive can occur at the level of the medullary controller due to drugs, stroke and blood gas changes
- For example:
- Patients with opiate overdose often present with loss of consciousness with a low respiratory rate (<10 bpm)
- Other features include pin-point pupils and low blood pressure
- Can be readily reversed with naloxone but infusions are often required
Draw a diagram to illustrate reduced compliance in kyphoscoliosis.
Give experimental evidence for the best indicators of motor neuron disease.
(Polkey, 2017):
- Plotted vital capacity and diaphragmatic strength (as determined by a sniff test) against time before death or non-invasive ventilation
- Found that diaphragm strength declined much earlier and more gradually than vital capacity in motor neuron disease
- This suggests that specific indicators of diaphragm muscle strength are better predictors of motor neuron disease than non-specific measures
Draw a volume against pressure curve for the lungs during normal breathing.
Draw a volume against pressure graph for restriction in COPD.
The work of ventilation is increased because the area of inspiration (the dark grey area) is larger.
Draw a volume against pressure graph for obstruction in COPD.
The work of ventilation is increased because the area of expiration (the black area) expands beyond the area of elastic recoil, so work needs to be done.
What are the two classifications of COPD?
How does lung hyperinflation happen in COPD?
- In health expiration is mainly due to the elastic recoil of the lung
- In COPD, reduced elastic recoil (emphysema) and airways resistance limit expiratory flow
- Expiratory flow is dependent on time -> Particularly when exercising this can lead to hyperinflation due to insufficient exhalation times
- In health, breathing occurs on the steep part of the pressure-volume curve
- In COPD hyperinflation right-shifts breathing so it is occurring on a less favourable part of the curve
- Note compliance (steepness of the slope) is not reduced in COPD (since it is more of an obstructive than restrictive disease)
Why can oxygen supplementation be a problem in COPD?
HPV:
- Turns off HPV, which is a protective mechanism for V/Q mismatch
- This means that elevated CO2 levels in underventilated lung units now increase PaCO2 levels
- Hence, the oxygen supplementation precipitates hypercapnia
Haldane effect:
- When PO2 is increased, it leads to a rightwards shift of the CO2 dissociation curve
- This means that for any given carbon dioxide content, PaCO2 is increased
- Hence, the oxygen supplementation precipitates hypercapnia
Loss of hypercapnic drive to breathe:
- Patients with hypercapnic COPD may over time lose their sensitivity to CO2 compared to normocapnic COPD
- This means that, in these patients, their ventilatory drive may be maintained mostly by hypoxia
- Hence, oxygen supplementation may lead to a loss of ventilatory drive, since they are no longer hypoxic
Give some experimental evidence for the importance of NIV in treatment of acute exacerbations of COPD.
(Plant, 2000):
- Compared use of NIV in treatment of acute exacerbations of COPD, compared to the best alternative management
- NIV led to a:
- Decrease in mortality of 48%
- Decrease in rate of intubation of 59%
- Decrease in hospital stay of 3 days
Give some contraindications against NIV.
Give experimental evidence for the use of NIV in motor neuron disease.
(Bourke, 2006):
- Studied patients with MND and either orthopnoea, daytime hypercapnia or reduced respiratory muscle strength
- Compared survival and quality of life when NIV was used compared to standard care
- NIV improved quality of life and survival
