Theme 3: Respiratory Physiology

Question 1

What is the difference between P_aO2 and P_AO2?

Answer 1

• P_aO2 -> In arterial blood
• P_AO2 -> In alveoli

Question 2

Draw a graph of how P_AO2 and P_ACO2 change with ventilation.

Answer 2

Question 3

What is a simple indicator of hyperventilation?

Answer 3

• A low P_ACO2
• This is because hyperventilation is one of the only causes of a low P_ACO2 (although a high P_ACO2 has many causes)

Question 4

Write out the alveolar gas equation.

Answer 4

P_AO2 = P_IO2 - (P_aCO2/0.8)

(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.)

Question 5

What important measure does ABG analysis allow to be calculated?

Answer 5

• It enables the A-a (Alveolar-arterial) P_O2 gradient to be calculated
• This is because the arterial P_O2 is directly measured, while the alveolar P_O2 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

Question 6

Summarise the two types of respiratory failure.

Answer 6

• Type 1 respiratory failure -> Gas exchange failure
• Type 2 respiratory failure -> Ventilatory failure

Question 7

Draw a graph to explain type 2 respiratory failure.

Answer 7

• Type 2 respiratory failure is ventilatory failure, where the lungs do not ventilate hard enough
• This means that P_aO2 is low (less than 8kPa), while P_aCO2 is high (more than 6kPa)
• The A-a gradient remains small, since there is no problem with gas exchange in the lungs

Question 8

What are some ways in which type 2 respiratory failure may be treated?

Answer 8

• Naloxone (opiate antagonist) -> This is because opiates can cause ventilatory failure
• Non-invasive ventilation (NIV)
• Invasive mechanical ventilation

Question 9

Draw a graph to explain type 1 respiratory failure.

Answer 9

• Type 1 respiratory failure is gas exchange failure -> Ventilation is increased, if anything
• This means that P_aO2 is low (less than 8kPa) AND P_aCO2 is also low (less than 6kPa)
• The A-a P_O2 gradient is greatly increased, but CO₂ is less affected

Question 10

Name some conditions that can feature type 1 respiratory failure.

Answer 10

• Asthma
• COPD
• Pulmonary fibrosis
• Acute respiratory distress syndrome (ARDS)

Question 11

Describe the epidemiology, pathophysiology, diagnosis and treatment of asthma.

Answer 11

• 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

Question 12

Give experimental evidence for how type 1 respiratory failure occurs in asthma.

Answer 12

(McFadden, 1968):

• Performed ABG analysis in patients during an asthma attack
• Plotted arterial P_O2 against percentage of the predicted FEV1 achieved by the patient -> Found that there was a linear relationship where decreased FEV1 led to lower arterial P_O2
• This would seem to suggest that the arterial P_O2 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 P_aCO2, which is associated with very low FEV1
• Instead, respiratory failure in asthma is thought to be due to V/Q mismatch (and P_aCO2 is high)

Question 13

Is V/Q mismatch compensated in terms of oxygen and carbon dioxide?

Answer 13

• 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

Question 14

What is COPD?

Answer 14

COPD = Emphysema and chronic bronchitis

• (Usually) smoking-related airflow limitation due to chronic airway inflammation and alveolar wall destruction.
• It is not fully reversible.

Question 15

Describe the three compartment model of V/Q mismatch.

Answer 15

• 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 P_CO2 against P_O2
• 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

Question 16

How does V/Q ratio change throughout the lung?

Answer 16

• 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

Question 17

Describe a technique to quantify the distribution of V/Q ratios throughout the lungs.

Answer 17

MIGET:

1. Infusion of a mixture of six inert gases* for 20-30 min
2. Sample of mixed venous blood from a Swan Ganz catheter
3. Sample of arterial blood (usually from the radial artery)
4. 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.

Question 18

How does COPD appear on a MIGET reading?

Answer 18

• 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

Question 19

Is 100% oxygen infusion a good idea to combat COPD and asthma? Give experimental evidence.

Answer 19

(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

Question 20

What is pulmonary fibrosis and how does it lead to type 1 respiratory failure?

Answer 20

• 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

Question 21

What is ARDS?

Answer 21

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

Question 22

What is the best treatment for ARDS and how is this optimised?

Answer 22

• 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.

Question 23

Does shunt improve with oxygen therapy?

Answer 23

No

Question 24

What are the two main types of pressure in the lungs?

Answer 24

• Intrapulmonary pressure
• Intrapleural pressure

Question 25

What pressure keeps the lungs open?

Answer 25

* Transpulmonary pressure * This is the difference between the intrapulmonary and intrapleural pressures * It can be altered in pneumothorax, pleural effusion, asthma or COPD

Question 26

Draw a graph to show how intrapleural, intrapulmonary and trans-pulmonary pressures change during the ventilation cycle.

Answer 26

Question 27

What are the two main variables to consider in invasive ventilation (positive pressure ventilation)?

Answer 27

* Resistance * Compliance

Question 28

How is compliance relevant to invasive ventilation?

Answer 28

* 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

Question 29

How is resistance relevant to invasive ventilation?

Answer 29

It is a key determinant of flow.

Question 30

Write an equation for flow during invasive ventilation.

Answer 30

This means that flow through the endotracheal tube can be increased by: * Increased radius * Decreased length * Increased pressure gradient

Question 31

What are some conditions that can involve reduced lung compliance?

Answer 31

* Pulmonary oedema * Pneumonia * Pulmonary fibrosis * Premature birth

Question 32

What is PEEP? Give details.

Answer 32

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

Question 33

What is total inspiratory pressure?

Answer 33

It is the total pressure required to deliver a desired volume in invasive ventilation.

Question 34

What is plateau pressure?

Answer 34

* 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

Question 35

What is mean alveolar pressure?

Answer 35

* It is the average pressure in the alveoli during the respiratory cycle * The higher the MAP, the more alveoli are open for gas exchange

Question 36

How can mean alveolar pressure be increased?

Answer 36

1. Increasing inspiratory pressure 2. Increasing time spent in inspiration 3. Increasing the PEEP

Question 37

What are the indications for invasive ventilation?

Answer 37

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

Question 38

What are the main benefits of invasive ventilation?

Answer 38

1. Improve oxygenation 2. Clearance of carbon dioxide 3. Reduced work of breathing

Question 39

What are some consequences of invasive ventilation?

Answer 39

* 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

Question 40

What is the problem with spending too long in inspiration?

Answer 40

It can lead to CO₂ retention.

Question 41

What are the different forms of ventilator-associated lung injury?

Answer 41

* 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

Question 42

Give some experimental evidence for how invasive ventilation can be optimised.

Answer 42

(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

Question 43

Describe the parameters of lung-protective invasive ventilation.

Answer 43

* Maintenance of plateau pressure \< 30 cmH2O * Tidal volumes ≤ 6 ml/kg * Application of PEEP to reduce alveolar opening-collapse

Question 44

What are the two main modes of invasive ventilation?

Answer 44

* Pressure control (pressure generator) * Flow/volume control (flow generator) Note: Volume and flow are interchangeable (as V = Q x t).

Question 45

Describe volume controlled ventilation.

Answer 45

* 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.

Question 46

Describe pressure controlled ventilation.

Answer 46

* 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

Question 47

How can oxygenation during invasive ventilation be improved?

Answer 47

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

Question 48

How can the CO₂ be effectively cleared during invasive ventilation?

Answer 48

* Increase alveolar minute ventilation * Permissive hypercapnia may be required

Question 49

Where are the peripheral and central chemoreceptors?

Answer 49

* Peripheral chemoreceptors -\> Carotid bodies (at the bifurcation of the common carotid artery) * Central chemoreceptors -\> In the brainstem

Question 50

Describe the innervation of the carotid body.

Answer 50

* Innervated by the carotid sinus nerve * These nerves originate in the petrosal ganglia and project back to the NTS in the brainstem

Question 51

What does the carotid body sense?

Answer 51

* It is mostly responsive to oxygen * But it is also sensitive to CO₂ and pH to a lesser extent

Question 52

Describe the structure of the carotid bodies.

Answer 52

* 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

Question 53

Give some experimental evidence for the role of type 1 cells in the carotid body.

Answer 53

(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

Question 54

Give some experimental evidence for the importance of ATP transmission in the carotid body.

Answer 54

(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

Question 55

Give some experimental evidence for how chemoreception in the carotid body leads to neurotransmitter release.

Answer 55

(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

Question 56

What leads to calcium influx during hypoxia in type 1 carotid body cells? Give experimental evidence.

Answer 56

* 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

Question 57

What channels are responsible for sensing of hypoxia in type 1 carotid body cells? Give experimental evidence.

Answer 57

* (Buckler, 2000): * Identified a type of potassium channel active at the resting membrane potential with a lower open probability during hypoxia * Found that the general properties were consistent with the acid sensitive (TASK) subgroup of channels * (Kim, 2009): * Single channel analysis suggests mixture of TASK-1, TASK-3 and (predominantly) TASK-1/TASK-3 heteromultimer * (Trapp, 2008): * Performed TASK1 KO and TASK1/TASK3 double KO on mice * In each of these KOs, the response to hypoxia (the CSN activity) was blunted * The same was seen with the response to hypercapnia * These results suggest that TASK channels are central to sensing of hypoxia in type 1 cells. However, other channels have been identified to play a potential role too. * (Peers, 1991): * Found that calcium-activated potassium currents (IK_Ca) are also blunted by hypoxia * (Lopez-Lopez, 1989): * Found that delayed rectifier potassium currents are also blunted by hypoxia * The problem with these last two currents is that neither is active at the resting membrane potential, so they are proposed to only play a role in adjusting the magnitude of the response to hypoxia. * (Buckler, 1997): * Used TEA and 4-AP to inhibit voltage-sensitive potassium channels * This had no effect of oxygen-sensing * Thus, this was further evidence that oxygen-sensing is predominantly due to voltage-insensitive background channels (TASK channels)

Question 58

Give a summary of oxygen sensing in type 1 carotid body cells.

Answer 58

* Hypoxia inhibits both TASK channels and, possibly, a calcium activated large conductance potassium channel (BK_Ca). * Inhibition of background (TASK) K⁺-current initiates membrane depolarization. Possible role for other, as yet unidentified, currents suggested by KO mice studies. * This depolarizing receptor potential may initiate electrical activity. * Voltage gated Ca-currents and Ca-activated cation currents promote further depolarization. Voltage gated K-channels and Ca-activated K-channels may oppose further depolarization. * Hypoxic-modulation of voltage and Ca-activated K⁺-channels may facilitate electrical signalling (actual role not yet confirmed/disputed). * Depolarization and electrical activity promote voltage-gated Ca²⁺ entry. * Rise in [Ca2+]_i promotes neurosecretion. * ATP (and possibly Acetylcholine and 5HT) excites afferent nerve endings.

Question 59

What leads to calcium influx during acidosis in type 1 carotid body cells? Give experimental evidence.

Answer 59

(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

Question 60

What channels are responsible for sensing of acidosis in type 1 carotid body cells? Give experimental evidence.

Answer 60

(Buckler, 2000): * Identified a type of potassium channel active at the resting membrane potential with a lower open probability during hypoxia * Also showed that this was acid-sensitive (see previous flashcard) * Found that the general properties were consistent with the acid sensitive (TASK) subgroup of channels (Tan, 2007): * Found evidence of another more minor current seen in response to acidosis * This is a transient inward cation current through ASIC (acid-sensitive inward current) channels * However, the current is only large at pHs lower than around 6, so it is not very physiologically relevant

Question 61

What is the importance of peripheral chemoreceptors detecting acidosis?

Answer 61

* While the central chemoreceptors do respond to increased CO₂, they do not detect pH changes directly. * This means that the response to metabolic acidosis is entirely driven by peripheral chemoreceptors.

Question 62

What are the main channels involved in response to hypoxia and acidosis in the carotid bodies?

Answer 62

* TASK 1/3 channels (which close during hypoxia or acidosis) * There are also other channels proposed, but the TASK channels seem to play the major role

Question 63

What are the main hypotheses for how oxygen-sensing in carotid body cells?

Answer 63

* Mitochondrial energy metabolism. * This is a long-standing hypothesis but it is not clear how the mitochondrial energy metabolism could be conveyed to the membrane channels (e.g. TASK) * Some ideas include: * ATP * AMP-Kinase * Lactate receptor * Complex 1 ROS generation * H₂S * H₂S as a gaseous signalling molecule * This could be either alone or in combination with CO * Potential to also link to the mitochondria hypothesis * NADPH oxidase * Largely forgotten * Heme oxygenase & CO as a signalling molecule * Should be forgotten

Question 64

Describe H₂S metabolism and how it is related to oxygen sensing.

Answer 64

* 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

Question 65

Give experimental evidence for and against the role of H₂S in oxygen sensing in the carotid body.

Answer 65

FOR (Peng, 2010): * Studied the effect of different concentrations of H₂S on carotid body activity * Found that higher concentrations of H₂S led to increased activity -\> In a calcium free environment, there was almost no activity * These results could be compromised by the fact that it is difficult to control the concentration of H₂S in solution * H₂S is an inhibitor of cytochrome oxidase, so this fits in with the hypothesis of a mitochondria-centred model of oxygen sensing * The authors argued that the H₂S is regulated by something upstream of the mitochondria, which leads to the question of whether the H₂S affects mitochondria or whether the mitochondria affect H₂S production (and this subsequently affects membrane channels) -\> In other words, is H₂S the end-point of oxygen-sensing? Does it come before or after the mitchondria? * Also showed that knock out of the H₂S-generating enzyme cystathionine γ-lyase blunts carotid sinus nerve activity AGAINST (Wang, 2017): * Compared cystathionine γ-lyase knockout mice with wild-type mice * There was no significant difference in the TASK channel closing or intracellular calcium change in response to hypoxia * There was also no difference in the ventilatory response to hypoxia * Therefore, this was a direct contradiction to the previous study * The authors suggested that the authors of the previous study may have made a mathematical error It is difficult to draw conclusions about the importance of H₂S because it can be produced by two different enzymes (so one could compensate for the other).

Question 66

Describe the heme-oxygenase-2 sensor model of oxygen sensing in the carotid body. Give experimental evidence for whether this is valid.

Answer 66

* 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

Question 67

Give experimental evidence for and against the role of the mitochondria in oxygen sensing in the carotid body.

Answer 67

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

Question 68

What are some possible links/signalling pathways that connect mitochondria and membrane ion channels in oxygen sensing in the carotid body?

Answer 68

* ATP * AMP-Kinase * Lactate receptor (Discredited, role for Olfr78 unknown) * Complex 1 ROS generation

Question 69

Give some experimental evidence for the role of AMP-kinase in linking mitochondria and membrane ion channels in oxygen sensing in carotid body cells.

Answer 69

* (Wyatt, 2007): * AMPK inhibition attenuates hypoxia- and AICAR-induced increases in carotid sinus nerve discharge * AICAR is a stimulant of AMPK * This suggests that AMPK plays an important role in oxygen sensing * (Mahmoud, 2015): * Conditional deletion of AMPK-α1 and AMPK-α2 genes has no effect on carotid body response to hypoxia. * This suggests that AMPK does NOT play an important role in oxygen sensing

Question 70

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.

Answer 70

​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

Question 71

Give some experimental evidence for the role of ATP in linking mitochondria and membrane ion channels in oxygen sensing in carotid body cells. Describe the model.

Answer 71

(Varas, 2007): * When a TASK channel is excise patched (in an inside-out configuration), the activity of the channel falls by about 90% within around 30 seconds * This loss of activity can be partly reversed by adding magnesium ATP * This suggests that the channels have some ATP dependence * The reason for this is not clear

Question 72

What parts of the brain control ventilation?

Answer 72

Parts of the medulla: * Ventral respiratory group * Mostly inspiratory neurons -\> Including the phrenic nerve and spinal nerves (intercostal muscles) * Also includes some neurons for forced expiration -\> Including spinal nerves (intercostal muscles and abdominal muscles) * Dorsal respiratory group * Mostly motor output to the upper airways -\> Larynx, pharynx, mouth, nostrils, etc.

Question 73

What are the main current theories of central rhythm (and pattern) generation in breathing?

Answer 73

* Emergent property of a neuronal network -\> In other words, the rhythm derives from reciprocal synaptic interaction/oscillation. * Pacemaker (or Noeud vital) -\> Neurons with intrinsic rhythmic activity. * Hybrid -\> Aims to integrate the previous two theories. Network with imbedded pacemaker cells.

Question 74

What are the main neural phases of normal ventilation?

Answer 74

* Expiration * Inspiration * Post-inspiratory / Early expiratory phase -\> This is a short burst of activity seen mostly in the phrenic nerve

Question 75

What are the different types ofrespiratory-related neurons in the ventral respiratory group?

Answer 75

* 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

Question 76

Describe the conditional network bursting theory three phase model of ventilatory control.

Answer 76

* 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.

Question 77

Draw phase 1 of the conditional network bursting theory three phase model of ventilatory control.

Answer 77

Question 78

Draw phase 2 of the conditional network bursting theory three phase model of ventilatory control.

Answer 78

Question 79

Draw phase 3 of the conditional network bursting theory three phase model of ventilatory control.

Answer 79

Note that there should also be pre-inspiratory neurons on this diagram that inhibit E2 and hence end phase 3.

Question 80

Describe a pacemaker model for ventilatory control. Give experimental evidence.

Answer 80

(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

Question 81

Give experimental evidence for a hybrid model of ventilatory control.

Answer 81

(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.

Question 82

Draw a hybrid model of ventilatory control.

Answer 82

* 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

Question 83

Describe an alternative hybrid model of ventilatory control.

Answer 83

* (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

Question 84

What do central chemoreceptors detect?

Answer 84

Question 85

Where are central chemoreceptors found?

Answer 85

In Mitchell's area, which is in the ventrolateral medulla.

Question 86

How can the site of central chemoreceptors be determined?

Answer 86

* By acetazolamide or CO₂ injections. * By acidosis induced c-Fos expression -\> c-Fos is expressed when cells become active, so acidosis shows which cells are active during acidosis.

Question 87

What are the effects of acidosis on inspiratory and post-inspiratory neurons? Give experimental evidence. What other cells are chemosensitive?

Answer 87

* (Kawai, 1996): * Studied neurons briefly exposed to 8% CO₂ * Inspiratory: * The cell depolarised and firing frequency increased * In the presence of TTX, firing frequency ceased but depolarisation still happened * This suggests that the cells are acid-sensitive * Post-inspiratory: * The cell hyperpolarised and firing frequency decreased * In the presence of low calcium and high magnesium (to block synaptic transmission), firing frequency ceased but hyperpolarisation still happened * This suggests that the cells are acid-sensitive * Other studies have also shown that there are highly chemosensitive neurons in the retrotrapezoid nucleus (near the parafacial respiratory group). Their firing rate increases with CO₂. These send dendritic trees that project to the surface of the medulla. * There are also acid-stimulated serotonergic medullary raphe neurons.

Question 88

Which of the central chemosensitive areas is most important for control of ventilation?

Answer 88

Congenital central hypoventilation syndrome (CCHS, a.k.a. Ondine’s curse) gives evidence for the idea that the retrotrapezoid nucleus is most important: * Failure of autonomic control of breathing. * Lack of response to CO₂ and hypoventilation. * Severe apnoea and respiratory arrest during sleep. * 91% of cases involve mutations in PHOX2b -\> This is a transcription factor found in neurons involved in autonomic/visceral control. * Phox2b^27ala/+ mouse models show severely disordered breathing and die soon after birth: * Loss of CO2 sensitivity in newborn. * Loss of glutamatergic neurons in RTN. * (Ramanantsoa, 2011): * Produced a targeted KO of PHOX2b in the retrotrapezoid nucleus * The KO mice showed almost no ventilatory response to CO₂, until they grow up to be adults -\> This could be due to peripheral chemoreceptors later in life * (Abbott, 2009): * Used optogenetics to test role of retrotrapezoid nucleus * A lentivirus expressing channelrhodopsin2 (ChR2) under the control of the Phox2-responsive promoter PRSx8 was injected into RTN. * This channel enables depolarisation of the cell. * Shining laser light on the cell during low CO₂ led to RTN cell activity and phrenic nerve activity.

Question 89

How does acidosis modulate the activity of chemosensitive neurons?

Answer 89

(Washburn, 2002): * Serotonergic neurons of the medullary raphe express TASK-1 & TASK-3 channels. * Inhibition of these channels lead to depolarisation and release of serotonin. (Wang, 2013): * Found that RTN cells express TASK-2 channels * TASK-2 channels are alkaline-sensitive * TASK-2 KO shows that a higher percentage of RTN cells are pH-insensitive when pH drops to 7.0 and rises to 8.0 * However, not all of the TASK-2 KO cells are pH-insensitive (Kumar, 2015): * KO of GPR4 (a GPCR) disrupted CO₂-evoked ventilatory stimulation and RTN neuronal activation in vivo. * Also increased incidence of spontaneous apneas. * In vitro, GPR4 deletionablates a pH-sensitive background K⁺ current in a subset of RTN neurons. Overall, deletion of TASK-2 and GPR4 has cumulative effects on chemosensing, so they are not involved in the same pathway.

Question 90

Give a summary of control of breathing.

Answer 90

Question 91

How does body position affect breathing?

Answer 91

When lying flat: * Diaphragm pushed cranially * If weakened, the diaphragm moves paradoxically cranially on inspiration Supine position also leads to: * Chest wall configuration altered * Intrathoracic pressure increases * Central shift of blood * Decreased compliance * Increased airway resistance

Question 92

Aside from body position, why does sleep predispose to disordered breathing?

Answer 92

* Muscle tone decreases * Accessory muscles drop out * Intercostals reduced tone * Reduced tone in pharyngeal dilators -\> The pharynx is a collapsible structure too * Breathing also lessens and becomes more regular

Question 93

What is obstructive sleep apneoa?

Answer 93

Intermittent pauses in breathing during sleep due to obstruction of the upper airway.

Question 94

What are apnoeas and hypopnoeas?

Answer 94

* Full apnoea = Complete cessation of airflow for more than 10 seconds) * Hypopnoeas = Partial reduction in airflow for more than 10 seconds

Question 95

What are the main types of apnoea?

Answer 95

* Obstructive * Central

Question 96

Describe the features of obstructive sleep apnoea.

Answer 96

* Hundreds of episodes of upper airway collapse overnight * Intermittent hypoxia, recurrent arousals, and increased intra-thoracic pressure swings * Increased sympathetic output with blood pressure surges up to 75mmHg * Sleep fragmentation

Question 97

Describe the cycle of obstructive sleep apnoea.

Answer 97

Question 98

Give experimental evidence for the mechanism of obstructive sleep apnoea.

Answer 98

(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

Question 99

What is the arousal stimulus to waking up in obstructive sleep apnoea?

Answer 99

* 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.

Question 100

What are the risk factors for obstructive sleep apnoea?

Answer 100

Anatomical: * Older age * Male gender * Obesity * Retrognathia (jaw pushed far back) -\> Decreases pharyngeal space * Large tonsils narrowing the upper airway (common in children) Non-anatomical: * Arousal threshold * Loop gain * Muscle responsiveness

Question 101

Why is obesity a risk factor for obstructive sleep apnoea?

Answer 101

* Increased neck size -\> Leads to external/extra-luminal compression of the upper airway * Increased size of upper airway structures due to fatty infiltration * Abdominal obesity -\> Compresses the diaphragm, particularly in the supine position

Question 102

Give experimental evidence for the importance of obesity in obstructive sleep apnoea.

Answer 102

(Sutherland, 2019): * Obesity is associated with neck size * Increasing neck size is a risk factor for OSA (across ethnicities) * External loading by fatty tissue surrounding the upper airway increases the likelihood of upper airway collapse. (Kim, 2014): * Performed MRI on OSA and normal patients * On average, OSA patients have larger, more fat tongues. * The tongue is the largest upper airway soft tissue structure and therefore its size is important in determining OSA risk. (Wang, 2020): * Used MRI images of the tongue to show the impact of weight loss on tongue fat and sleep apnoea severity. * This individual has lost of 50kg leading to marked reduction in tongue fat and a marked reduction in sleep apnoea severity

Question 103

How does abdominal and thoracic obesity affect obstructive sleep apnoea?

Answer 103

* Abdominal and thoracic fat causes external compression of lung volumes which reduces the functional residual capacity (FRC) * As well as potentially causing under breathing, this reduces traction on the pharynx (traction holds it open) which makes OSA more likely.

Question 104

How can we measure airway collapsability?

Answer 104

* Apply a pressure to the airway and plot it against airflow * The pressure at which the airway collapses is called P_crit * P_crit is higher in individuals with obstructive sleep apnoea

Question 105

Compare P_crit in individuals with obstructive sleep apnoea and healthy controls.

Answer 105

(Eckert, 2013): * Plotted P_crit 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 (P_crit above 2cmH₂O) and healthy controls have less collapsible airways (P_crit below 0cmH₂O) * However, there was overlap and significant variability within the 0-2cmH₂O P_crit range

Question 106

Describe how arousal threshold varies in healthy and obstructive sleep apnoea patients.

Answer 106

(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

Question 107

Why do some obese individuals not have OSA? Give experimental evidence.

Answer 107

(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.

Question 108

What is loop gain and how can it be measured?

Answer 108

* 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.

Question 109

Is a low loop gain or high loop gain better?

Answer 109

* 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.

Question 110

Give some experimental evidence for how obstructive sleep apnoea affects cardiovascular risk.

Answer 110

(Marin, 2005): * Compared 1651 patients, including: Healthy controls, simple snorers, untreated mild-mod OSA, untreated severe OSA, and treated severe OSA * The untreated severe OSA patients showed a 3 fold increased risk of both fatal and non-fatal CV events over 144 months * However, it is unclear whether the OSA is just a surrogate marker for something else here

Question 111

What is another name for central sleep apnoea?

Answer 111

Cheyne-Stokes Respiration

Question 112

What does central sleep apnoea involve?

Answer 112

* Periodic hyperpnoeas and hypopnoeas * “Stop-start” breathing * Without snoring

Question 113

What are three conditions in which central sleep apnoea may be common?

Answer 113

* Congestive cardiac failure * Stroke * Altitude

Question 114

Why might central sleep apnoea occur at altitude?

Answer 114

* 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

Question 115

Why might central sleep apnoea occur in congestive heart failure?

Answer 115

Significantly prolonged circulation times prolong the time to sensing the changes in carbon dioxide levels.

Question 116

Why is REM sleep a particularly vulnerable time for sleep apnoeas?

Answer 116

* During REM sleep, there is real paralysis, which spares only the eye muscles and diaphragm * This is due to activity of Jouvet’s centre in the brainstem * This leaves only the diaphragm with which to breath

Question 117

How is sleep apnoea treated?

Answer 117

Usually using a face mask to apply positive airway pressures.

Question 118

What are the benefits of CPAP in obstructive sleep apnoea?

Answer 118

* Improved symptoms * Reduced road traffic accidents * Lowers BP * Cardiovascular events

Question 119

Summarise type 2 respiratory failure.

Answer 119

* 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

Question 120

Draw a diagram to show the main causes of type 2 respiratory failure.

Answer 120

Question 121

Describe a model that can be used to understand type 2 respiratory failure.

Answer 121

* 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.

Question 122

Describe an example of how reduced drive can lead to type 2 respiratory failure.

Answer 122

* 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

Question 123

Describe an example of how increased load can lead to type 2 respiratory failure.

Answer 123

* Increased load can be due to: * Obesity * Kyphoscoliosis

Question 124

Draw a diagram to illustrate reduced compliance in kyphoscoliosis.

Answer 124

Question 125

Describe an example of how decreased capacity can lead to type 2 respiratory failure.

Answer 125

* Decreased capacity can be due to: * Problems with the lower motor neurons * Problems at the NMJ * Problems with respiratory muscles

Question 126

Describe motor neuron disease.

Answer 126

* Rare, progressive degenerative neurological condition affecting both upper and lower motor neurones * History: * Dyspnoea, orthopnoea, headache on awakening, morning confusion, poor sleep/sleepiness (ESS), witnessed apnoeas * Examination * Orthopnoea, abdominal paradox on breathing/sniffing, potentially low oxygen saturations

Question 127

Describe the tests for diaphragmatic weakness.

Answer 127

* Lying and Standing Spirometry -\> A greater than 15% fall in vital capacity when lying down is indicative of diaphragm weakness * Nocturnal oximetery -\> Oxygen falls during REM sleep * Oesophageal and gastric balloons during sniffing -\> The pressure generated by the diaphragm is equal to the gastric pressure (abdominal) minus the oesophageal pressure (thorax) during a sniff

Question 128

Give experimental evidence for the best indicators of motor neuron disease.

Answer 128

(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

Question 129

Why does COPD cause type 2 respiratory failure?

Answer 129

* Increased work of breathing * Increases in physiological dead space * VQ mismatch * Hyperinflation

Question 130

Draw a volume against pressure curve for the lungs during normal breathing.

Answer 130

Question 131

Draw a volume against pressure graph for restriction in COPD.

Answer 131

The work of ventilation is increased because the area of inspiration (the dark grey area) is larger.

Question 132

Draw a volume against pressure graph for obstruction in COPD.

Answer 132

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.

Question 133

What are the two classifications of COPD?

Answer 133

Question 134

How is dead space affected in COPD?

Answer 134

* There is anatomical dead space * But there is also physiological dead space due to impaired gas exchange

Question 135

How does lung hyperinflation happen in COPD?

Answer 135

* 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)

Question 136

Why can oxygen supplementation be a problem in COPD?

Answer 136

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

Question 137

Describe how non-invasive ventilation works for type 2 respiratory failure.

Answer 137

* Utilises positive pressure * During expiration, holds the pressure at a low constant level * When the patient attempts to take a breath, the machine detects this and drives the pressure up to a high pressure for inspiration * This then repeats Details: * Indications: decompensated hypercapnic respiratory failure, unlikely in COVID-19 * Oxygen flow rate: unknown but high- flow (up to 200 L/min) only with V60 * FiO2: low-flow unknown but max ~60% with 15 L/min, V60 ~100% * Pros: reduces need for intubation * Cons: limited availability, aerosol generating

Question 138

Describe COPD exacerbations and their management.

Answer 138

* Account for 20% of admissions with acute hypercapnic respiratory failure (T2RF) * Mortality from COPD exacerbations is 8% rising to 30% with T2RF * The first step is trialling one of medical management * Controlled oxygen using a venturi mask to keeps saturations 88-92% * Bronchodilator therapy: salbutamol 2.5mg nebulised back-to-back and 500mcg ipratropium nebulised once * Prednisolone 30mg PO or hydrocortisone 100mg IV * Antibiotics as per guidelines if appropriate * When medical management fails intubation used to the be the only option

Question 139

Give some experimental evidence for the importance of NIV in treatment of acute exacerbations of COPD.

Answer 139

(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

Question 140

Give some contraindications against NIV.

Answer 140

Question 141

Give experimental evidence for the use of NIV in motor neuron disease.

Answer 141

(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

Question 142

Give experimental evidence for the use of NIV in obesity hypoventilation syndrome (without obstructive sleep apnoea).

Answer 142

(Masa, 2020): * Compared PaCO₂ and HCO₃^- in obesity hypoventilation syndrome when NIV was and wasn't used * NIV reduced both PaCO₂ and HCO₃^-