Respiratory Physiology

Lecture 2: Ventilation

• Respiratory volume: (symbol V). This factor is dependent on temperature, barometric pressure and water vapour pressure hence all measurement is readjusted to standard conditions, i.e. 0oC, 101.3kPa, dry (zero humidity).
- Total lung capacity: total volume possible of the lung when maximally expanded
- Vital capacity: volume of air that the lung can potentially operate with, e.g. expire and inspire fully
- Residual volume: minimum volume the lung can achieve, i.e. volume of air that can never be exhaled
- Tidal volume: volume of air inspired and expired during normal ventilation
- Expiratory reserve: the volume of air that can be forcibly expelled by active compression of chest muscles and diaphragm at the end of expiration of tidal volume
- Functional residual capacity: volume of air present in the lung at the end of normal expiration, i.e. expiratory reserve + residual volume
- Inspiratory reserve: volume of air that can be drawn into the lung from the end of normal inspiration by forceful lowering of the diaphragm and expansion of chest wall.
• Capacity: a sum of two or more volumes
• Adjusting for standard conditions:
- Standard temperature: V(ST) = V(AT) × 273/273+T where T is recorded temperature
- Standard pressure: V(SP) = V(AP) × PB/760 where PB is recorded pressure
- Dry condition: PB – Psat (expired air) where Psat is vapour pressure for the recorded temperature
- Overall:
V(STPD) = V(ATPS) × 273/273+T × (PB-Psat)/760
• Flow: (symbol L min-1)
- Minute volume: volume of pulmonary ventilation per minute
- Normal ventilation rate is measured by tidal volume × frequency of breaths ( = VTf)
• Anatomic dead space: the volume of the conducting airway of the respiratory tree in which gas exchange does not occur. It usually occupies one-third of the tidal volume and is obligatory for tidal ventilation
- Inspiration: during inspiration, it represents the volume of fresh air that is trapped within the conducting pathway and is not used
- Expiration: during expiration, it represents the volume of used air that can not be expelled in the conduit and hence will dilute (“pollute”) the fresh air of the next inspiration. The expired air will consisted of 2 part alveolar air and 1 part unused air.
• Physiological consequence of dead space: the component of tidal volume that did not participate in gas exchange. This may differ from the anatomic dead space as there are more factors present that inhibit efficient usage of inspired air but in health individuals, physiological dead space approximate anatomic dead space.
• Quantification of physiological dead space: based on the assumption that fraction of CO2 in inspired air is approximately 0 and that VT = VA + VD and VT = VE where VE is the total volume of expired air in a normal breath.
- Step 1: VECO2 = VACO2 + VDCO2 (total volume of expired CO¬2 is made up of CO2 from alveolar and dead space)
- Step 2: VE×FECO2 = VA×FACO2 (as dead space has no CO2, VDCO2 can be removed and equation expresses the idea that volume of CO2 of a space is the product of the volume with the fraction of CO2 in that space)
- Step 3: VE×FECO2 = (VT – VD) ×FACO2 (¬volume of alveolar ventilation is difference of tidal volume and dead space)
- Step 4: VD = VT × (tidal volume is the volume of expired air so interchangeable)
- Explanation: the final equation simply express the idea that due to the dead space (VD), the tidal volume of CO2 volume is not completely alveolar air (VT× FACO¬2 ) but reduced to the amount of VT × FECO2 due to the dead space volume with no CO2, i.e. VD dilutes FACO2 to FECO2
• Pressure expression: as volume is directly proportional to pressure under constant temperature:
VD = PACO2 = VT
- Since arterial pressure of CO2 approximate that of alveolar pressure of CO2, i.e. PaCO2 ≈ PACO2:
VD =
- Final Bohr equation:
=
• Conditions of flow: from A to B
- Pressure of A is greater than pressure of B
- Resistance to the flow is finite
• Laminar flow: smooth flow of fluid in which the layers do not mix and travel at different velocities
- Poiseuille-Hagen Law: V = where R is resistance proportional to ηl/r4 (η is viscosity, l is length and r is radius)
- In laminar flow, flow rate is proportional to difference in pressure
• Turbulent flow: disturbed flow of fluid with unstable mixing of layers and velocity of flow is greatly compromised.
- In turbulent flow, flow rate is proportional to the root of the difference in pressure hence a much greater difference in pressure is needed to reach a certain flow rate than laminar flow
• Reynolds number: Reynold’s number is determined by the where ρ is density, and v is velocity. If reynold’s number exceeds the critical value of around 2000, then laminar flow will change into turbulent flow. Hence smaller the density, radius of tube and slower the flow, the lower the probability of turbulence
• Effect of branching: as the airways bifurcate, the radius of the channels decreases but the total cross-sectional area of each level increases, hence air way resistance and flow rate decreases exponentially.

Lecture 3: Mechanics of Ventilation

• Pressures of inspiration: lowered diaphragm or increased rib cage causes alveolar pressure to become subatmospheric and flow of air is inwards, i.e. α PB - PA.
• Forces on the lung: elastic forces of the tissue
- inward collapsing force of alveolar (lung)
- outward expansion force of the chest wall (ribcage)
- Functional residue capacity: volume of the lung at which the two forces are balanced
• Intrapleural space: the lung is covered with visceral pleura while the chest is lined with parietal pleura and the two are not physically connected, hence creating a space of serous fluid free to move.
• Intrapleural pressure: pressure established within the intrapleural space (around 5mmHg) and is subatmospheric at FRC. Generate compressive positive pressure with active expiration
- Inspiration: during inspiration, the diaphragm is lowered increasing the thoracic volume and as a result, intrapleural pressure becomes more negative pulling the lung and alveolar open
- Expiration: rising of diaphragm decrease thoracic volume and generate compressive forces on the lung causing intrapleural pressure to increase and alveolar collapses
- FCR: Pip < PB at this point
• Pneumothorax: a condition in which a hole is created in the pleural space and due to the negative pressure of the pleural space, air rush in causing the space to expand and the lung to collapse completely. The patient is unable to inflate their lung and inspire.
• Elasticity: Hooke’s Law where the displacement of one-dimensional body is proportional to the restoring force. So expanding the lung from the residue volume creates the inward elastic force.
• Compliance: inverse of elastance of the three-dimensional body - ∆V = C ∆P where C is the measure of compliance, the ease of change of the volume of the body in response to a pressure
- Units of compliance: L/cmH2O
- Factors of compliance: tissue stretchability and air-water surface tension
• Specific compliance: measurement of compliance which takes into account for the differences in compliance of the lung at different lung volume, i.e. larger lungs volume the more compliant. Hence measuring compliance per unit of volume.

Cspecific =

• Total lung compliance: takes into account of all factors that may affect lung compliance such as air-water surface tension.
• Factors decreasing lung compliance:
- pulmonary fibrosis: elastic fibers will reduce compliance
- alveolar oedema: water in lung parenchymal from elevated pulmonary venous blood pressure
- atelectasis: complete collapse of the alveoli
- deficiency of pulmonary surfactant: loss of ability to overcome surface tension
- chest wall rigidity: any factor contribute to stiffness of thorax
• Laplace Law: relating tension of an elastic body to the pressure it generates at a particular radius, i.e. at a specific size the alveolus will generate a certain pressure as the wall tension of the alveolar are all constant.

P =

- Decreasing radius of curvature increases pressure. When an alveolus reduces from a circle down to a semi-circle at the end of the bronchiole, pressure produced increases causing air flow. However as it reduces further forming only a curvature, the radius increases and the pressure drops rapidly.
• Air water surface tension: as a result of Laplace’s law, to blow up an alveolus from only curvature, to semi circle, pressure required is the greatest and volume change is minute (i.e. poor compliance). However as the alveolus inflate from semi-circle to “circle”, compliance increases and the lung expands with little pressure until it is countered by the elastic force of the tissue.
- hysteresis: due to surface tension and tissue elasticity, the compliance of lung during inflation is sigmoidal while deflation its curved.
• Compliance of chest wall and lung: chest wall is always subatmospheric as its tendency is to expand while the lung’s tendency is always to collapse hence positive airway pressure
- At extreme low airway pressure, the resultant volume of the lung is same as that of the minimal volume the chest wall can be compressed to (this is the residual volume). The lung is held at the residue volume and not allowed to collapse to minimal volume
- As the chest wall is allowed to recoil and lungs expand (e.g. during inspiration), airway pressure increase (pressure needed to keep the lung inflated) while the negative pressure in the chest is relieved.
- The two forces is balanced when the volume of the lung reaches the functional residue capacity
- Beyond the FCR as the chest wall continues to recoil, positive pressure of the airway increase (i.e. need greater pressure to keep the airway open against the collapsing force of lung)
- At high airway pressures, the chest wall reaches its equilibrium point and the lung capacity is sitting at the same volume as the lung itself
- Beyond the resting volume of the chest, recoil becomes inward which contributes to alveolar elasticity and increased positive airway pressure.
• Contribution of Lung compliance to regional-variation of ventilation: Compliance of the lung behaves in a fluid like nature
- In the upright posture, the lung is suspended in gravitation
- As a result, intrapleural pressure decrease in a graded manner from top to the bottom of the lung
- Alveolar at the bottom of the lung is experiencing smaller intrapleural pressure and hence more compressed (smaller diameter) while the vice versa occurs at the top of the lung
- Since compliance is greater for smaller volumes of alveolar, ventilation at the base is the greatest (larger change in volume for a given pressure)
• Airway collapse during forced expiration: alveolar ducts invaginate into alveolar hence the ending section of the duct is intrapulmonary.
- Pre-inspiration: during pre-inspiration, lung is collapsed and there is no flow of air, hence at this point the alveolar is at barometric pressure while the intrapleural pressure is -5mmHg.
- During inspiration: expansion of chest increases intrapleural pressure reaching a value of -7mmHg making the alveolar pressure now – 2mmHg. Since atmospheric pressure is 0, the pressure around middle of the respiratory airway is around half or -1 mmHg in this case. This produce a +6mmHg pressure in the airway to keep it open.
- End-inspiration: alveolar is expanded with intrapleural pressure sitting around 8mmHg and airway pressure is atmospheric since there is no more flow of air
- Forced expiration: by applying muscle action to force air out, intrapleural pressure will be greatly increased becoming positive (i.e. compress the lung). Example, if intrapleural pressure increases to +30mmHg, airway pressure will be 38mmHg. However along the airways, pressure diminishes toward zero and as soon as the airway pressure drops below that of intrapleural pressure, the airway will begin to collapse.
• Flow patterns of forced expiration: as a result of the mechanism above, following occurs
- Rapid exhalation: maximum expiratory effort from TLC. Higher flow rate is achieved as at higher volumes, the lumen of the airways is dilated and hence requires greater intrapleural pressure to collapse. Once intrapleural pressure exceeds that of airway and flow rate declines at a constant rate
- Slow exhalation: flow rate is limited and the lung decrease from TLC to a smaller volume where maximum respiratory effort is applied. Due to the smaller volume, airway would be slightly smaller, hence lower peak flow rate will be reached before collapse. Afterwards, flow rate decrease at a constant value.
- Very slow exhalation: flow rate is kept low and lung collapse slowly. When a very low volume is reached, maximum expiration occurs with a rapid rise in flow rate. However the airway collapse almost immediately and peak flow rate is low and decreases constantly afterwards
- Explanation: the same rate of drop off is due to the collapsed airway in which flow becomes independent of effort

Lecture 6: Dynamics of Ventilation

• Pressure and ventilation: ventilation of the lung, occurs when the difference in pressure between the airway opening and the alveoli. Factors that must be overcome in order for airflow:
- tissue compliance C
- resistance to flow of air in the airway R
• Equation of motion: equation of ventilation that relates both independent factors of resistance and compliance to flow rate as a result of pressure.

∆P = + R

- If flow rate is minimal, then the effect of resistance is minimal, i.e. a lower pressure can then achieve a higher change in volume
• Measurement of intrapleural pressure: approximated using pressure from the oesophagus. Used to measure pressure differences.
• Alveolar pressure and airflow: during inspiration, inflow of air is produced by the increasing intrapleural pressure to above that of the elastic pressure of the lung and this leads to the development of resistive pressure. This resistive pressure is in fact alveolar pressure produced to cause flow rate. Resistive/alveolar pressure along with flow rate peaks half way through inspiration and then decreases back to 0. Expiration is similar however everything is the opposite.
• Intrapleural pressure and airflow: when flow rate of air is minimum, intrapleural pressure decreases with inspiration to a maximum of -6 cm H2O at end of inspiration and restores back to normal with expiration. With air flow comes resistance and hence intrapleural pressure is requires to be greater at each point to overcome the resistance (i.e. phase shift of intrapleural/airflow).
- If we breath slowly, then Pip is close to that of the elastic pressure
• Pressure volume graph: with increase flow of air, greater pressure is required to overcome the resistance and achieve the same volume and as a result, the cycle/graph is wider.
- The gradient of the line joining the two points on the pressure volume graph in which flow rate is 0 (i.e. minimal volume to maximum volume) is the compliance. To RHS of the line is inspiration while to LHS is line of expiration.
• Work of breathing: during inspiration, active contraction of muscle is requires against a variable load (due to resistance) and this produces external work. When there is minimum air flow (hence resistance), work is only done to overcome the elastance of the lung and is constant.
- Expiration is a passive process during resting conditions from the elastic energy stored in the lung, e.g. when the loop of the expiration is contained within the area of stored elastic energy. However with active process of expiration, additional energy is used, i.e. when intrapulmonary pressure raises past 0.
- Total work done per cycle of breath is the work of inspiration while total work to overcome air resistance is the area of the loop (deviation left and right of the constant elastance)
• Effect of frequency on resistance and compliance:
- Resistance: with increase frequency, resistance increases proportionally due to faster breathing and flow rate
- Compliance: compliance relates inversely proportionally with frequency as at lower breathing rates, the lung needs to expand to greater volumes
• Tests of lung function:
- Forced vital capacity: maximum amount of air able to be exhaled with all effort
- Forced expiratory volume: maximum amount of air able to be exhaled in the first 1 second
• Flow rate against volume: flow rate increase rapidly and peaks around 25% of vital capacity and progressively drops away.
- Obstructive lung disease: the flow rate does not reach normal maximum and drops off much more rapidly than normal.

Lecture 7: Diffusion

• Diffusion: movement of gas particle from area of high concentration to areas of low concentration. However in respiratory context, partial pressure is used and is representative of concentration.
• Partial pressure: the pressure exerted by one specific gas under certain conditions (component of the total environmental pressure), i.e. PO2 = FO2 × PB
• Henry’s Law: states that concentration of dissolved gas is dependent on the solubility of the gas and its partial pressure (driving force) under constant conditions of temperature

C = σP where C is concentration, σ is solubility (mol/LkPa) and P is partial pressure

- When there is no overall loss of gas from solution, then the pressure present to keep the gas dissolved is the partial pressure for that condition, i.e. PO2(liquid) = PO2(gas)
• Solubility: CO2 readily dissolves in blood while O2 is highly insoluble (only 3mL per L). At the same partial pressure, CO2 dissolve 8 times more than O2.
• Role of partial pressure: the continue replenishment of oxygen and removal of carbon dioxide depends solely on diffusion driven by the partial pressure gradient of the gases.
• Fick’s law of diffusion: allows calculations of the rate of diffusion depending on its governing factors – diffusivity, solubility, driving pressures, surface area and diffusion distance.

O2 = A

Where D is diffusivity and σ is solubility of oxygen in alveo-capillary membrane.
• Diffusion conductance: since none of the factors that affect diffusion can be measured directly, the four unknown constant can be combined to a single term called diffusive conductance DL and so:

O2 = DL (PAO2 – PcO2)

• Measurement using CO: CO is usually the test gas for diffusivity and condition of lung. This is because CO binds to haemoglobin with great avidity, hence there are minimal CO dissolved in the blood and re-circulation back to lung does not occur, i.e. PCCO is approx 0. Also solubility of CO is comparable to O2. Overall:

DL =

• Perfusion limitation: the content of the gas in the blood is dependent entirely on the rate of blood flow due its high solubility causing rapid saturation. Arterial partial pressure for that gas increases to maximum to opposite the alveolar partial pressure for diffusion.
- Both N2O and normal O2 are perfusion limited especially N2O with rapid saturation
• Diffusion limitation: the poor solubility or rapid “removal” of the gas in the plasma means the arterial content of the gas is dependent only on the diffusion properties/rate. Arterial partial pressure will hardly increase and diffusion is at maximum (i.e. no opposing)
- CO is diffusion limited as practically all molecules are bound by haemoglobin
• Abnormal O2 uptake: perfusion/diffusion graph reveals a stead sloping increase in arterial partial pressure of O2 possibly as a result of poor lung tissue conditions, i.e. it is neither perfusion limited (does not saturate) nor diffusion limited (does not diffuse well)

Lecture 8: Oxygen Cascade

• Oxygen cascade: progressive decrease in the content and partial pressure of oxygen as it pass from the atmosphere to the mitochondria of the cells for aerobic respiration. 6 main process are responsible:
- Dilution by humidity
- Dead space dilution and CO2 mixing
- Sustaining of diffusion
- Capillary shunts and mixing
- Arterial to venous drop
- Diffusion into mitochondria
• Atmospheric oxygen: at sea level, partial pressure of oxygen is 160 mmHg
• Humidity dilution: as air passes down the airways, it becomes saturated with moist due to the wet environment. At 37oC body temperature, saturated vapour pressure contribute to around 47 mmHg. Since alveolar partial pressure can not be greater than atmospheric (otherwise air can not flow in), the humidity displaces oxygen and the partial pressure drops to around 150 mmHg:

PIO2 = FIO2 (PB – Pwater) = 0.209 (760 - 47) ≈ 150 mmHg

• Dead space dilution: the presence of the anatomic dead space will mean around 1/3 of the partial pressure of oxygen is lost (leave around 100 mmHg). This can be shown mathematically:
- The flow rate or rate of oxygen uptake must be the difference between the rate of oxygen inspired and oxygen expired.
- Therefore:
This equation includes the effect of “un-exchanged oxygen” occupying the anatomic dead space, i.e. with a value of 0.165 is higher than that the alveolar partial pressure fraction of O2 as pure oxygen in the anatomic dead space would mix during expiration and increase the oxygen content.
- Alveolar ventilation: to remove the effect of anatomic dead space, a new equation is implemented
oxygen in the anatomic dead space is unused, thus the 270 mlmin-1 of oxygen uptake must lie solely within the alveolar. Hence removing the dead space volume from tidal volume (VT – VD) will leave only the “effective” volume and the oxygen content for this space (FAO2) can be worked out. The result is the partial pressure fraction of O2 after dead space dilution.
- (i.e. 0.145/0.21 of O2 never used)
- So partial pressure of oxygen in the alveolar is
• CO2 mixing: arterial chemoreceptors regulate PaCO2 at a value of 40 mmHg and this contributes to further PAO2 dilution.
• Diffusion resistance: due to the low solubility of oxygen in plasma, a partial pressure gradient exists between alveoli and systemic arterial blood. The loss of PO2 is exacerbated by any pathological state that decreases DL
• Red blood cell transition time: arterial content of a specific gas and the degree of saturation of a RBC depends on its transit time through a capillary. Shorter capillary and faster flow will produce less saturation.
• Arteriovenous shunts: dilution of PaO2 as a result of mixing of deoxygenated blood with oxygenated blood through a “shunt”
- If there is no shunt the total amount of oxygen leaving he pulmonary capillaries would be where is the total blood flow and is fraction of oxygen in blood at the end of pulmonary capillaries.
- However as a result of shunt flow , total oxygen content is composed of which is the oxygen content of shunt flow (same as venous blood content) and also which is the non-shunt blood oxygen content at end of pulmonary capillaries.
- Final equation rearranged to
• Anatomic shunts: structural mechanism in which venous blood bypass the lung
- Component of bronchial circulation
- Thebesian component of the coronary circulation
- Pulmonary arteriovenous fistula
- Patent ductus arteriosus
- Patent foramen ovale
• Physiological shunt: any factors that contributes to venous blood mixing with pulmonary capillaries
• Effect of shunt: healthy individuals only have 1-1.5% (2 - 4 mmHg) of cardiac output becoming shunts. However due to the oxyhaemoglobin equilibrium, loss of a minute content of O2 may confer huge losses in oxygen partial pressure (when oxygen is close to saturation). E.g. loss of 10 mL/L of O2 causes a 20 mmHg drop of pressure from 100.
• Consumption of O2: partial pressure drops from around 96 mmHg to 40 mmHg as oxygen diffuses out through the capillary bed providing cells with aerobic resources.
• Ventilation-perfusion mismatch: a situations in which ventilation and perfusion for different alveoli differs causing decrease efficiency in oxygen uptake.
- An alveolus that is well ventilated but have poor capillary blood flow will mean blood is well oxygenated (quality) but lacks quantity – high ratio
- An alveolus that is well-perfused but unventilated contributes to poor quality blood but sufficiency quantity – low ratio
- Ratio of 1 indicates perfect condition of perfusion and ventilation
- Consequently as oxygen content of blood leaving the lung is the weighted average the acinar, poor alveoli will diminish overall uptake and achieve lesser O2 partial pressure.

Lecture 9: Regional variation of the ventilation-perfusion ratio

• Gravitational effects: the dominant mechanism for the variation of both perfusion and ventilation within the lung. As the lung is highly compliant, its basal region is relatively compressed while its apical region is relatively stretched during upright position.
• Variation of ventilation:
- apical: weight of the lung acts downwards to expand the intrapleural cavity making the pressure more negative at the apex.
- Base: tissue weighing down on the base cause the intrapleural pressure to be less negative and the alveoli is more compressed.
- In relation to the equation of ventilation:

As alveoli at the base of the lung are more compliant than the apex, according to the equation, this will confer a greater ventilation rate.
• Exceptions of the ventilation variation pattern: at very low volume of the alveoli, the intrapleural pressure tends toward 0 and positive, i.e. lung is compressed by the weight and the resultant ventilation is obviously 0. The compliance of the lung is almost zero as even with a change in pressure, it is insufficient to cause an increase in volume.
• RC time constant: resistance and compliance makes up the time constant for the system which is the time lag (shift) between pressure development and the resultant flow of air.
• Variation of pulmonary blood flow: due to effect of gravity in a 34cm height lung, the basal pulmonary capillaries will have 25 mmHg higher hydrostatic pressure than the apical capillaries. The variation can be observed if lung is divided into three zones top to bottom:
- Top zone: the lack of blood pressure (due to gravity) in the vessel means the lumen will collapse as a result of alveolar pressure causing poor perfusion
- Mid zone: blood pressure is high enough to sustain opening of the lumen against alveolar pressure but may have the venous end of the pulmonary capillaries collapse due to drop of blood pressure over the length. perfusion here is thus moderate
- Bottom zone: blood pressure is the highest with the aid of gravity which is higher than even that of alveolar pressure. Consequently, the vessels may even dilate allowing high perfusion.
• Measurement of blood flow: using oxygen consumption and consequent measurement of arterial O2 content and venous O2 content, flow of blood can be worked out.
- Oxygen uptake rate: in a steady state
- Circulation rate: as the rate of oxygen uptake must be contributing to the difference between the arterial and venous oxygen content. But the extent of difference depends on flow rate, i.e. high flow rate means less saturation so smaller difference.
- can be measured directly from mouth while and are measured using catheters placed in the brachial and pulmonary arteries respectively
• Pattern of ventilation and perfusion:
- Ventilation decrease from bottom to top due to decreasing compliance
- Perfusion decrease from bottom to top due to lack of blood pressure (against gravity)
• Distribution of ventilation-perfusion ratio:
- an impaired alveolar ventilation will cause the partial pressure to approach corresponding venous partial pressures, as there are no additional oxygen (O2 = 40 while CO2 = 45). The ratio is 0.
- Impaired blood flow will cause partial pressure to approach that of atmosphere as there is no uptake of oxygen (O2 = 150, CO2 = 0). Ratio is infinite.
- The graph plotting PCO2 against PO2 shows a downward curve with initial 0 gradient and progression to vertical gradient of infinity.
- The ratio increases from base of the lung to the apex as both ventilation and perfusion decreases but perfusion relatively more (i.e. perfusion decrease more than ventilation).
• Balancing the ventilation-perfusion ratio inequalities: the main mechanism is hypoxic vasoconstriction. Alveolar detects level of ventilation and constrict vessels that are underventilated to reduce perfusion while dilate vessels that are well-ventilated and increase perfusion.
- Experimental: areas of low ventilation or partial pressure of oxygen gains only a lower proportion of total blood flow.
• Consequences of hypoxic vasoconstriction:
- Increase of pulmonary arterial resistance: by reduction of low resistance parallel capillary branches
- Increase in arterial pressure: increased resistance will require higher pressure to pump the blood through
- Increase in workload of the right ventricle: ventricle operating at high pressure will develop right ventricular hypertrophy

Lecture 10: Lung function in exercise

• Transition of rest to exercise: rates of oxygen consumption and carbon dioxide production can increase 20-30 folds. This is the cumulative effect of many component of the system:

- : increase approx 20 times from 240 mL/min to 5L/min
- VT: increase 4 times from 0.5L to 2L
- Fresp: increase 3.5 times from 12 to 40 per min
- FIO2 – FEO2: increase 1.5 times (higher oxygen uptake)
- Vs: increase 2 times from 70mL to 150mL
- Fheart: increase 3 times from 70 to 200 per min
- CaO2 – CVO2: increase 3 times (higher saturation of RBC)
• Oxygen ventilation and work: an increase in rate of energy expenditure will cause our oxygen uptake rate to increase in a linear fashion until it reaches a point of “plateau” where oxygen uptake is at maximal rate. Increasing fitness and health allows for greater endurance and greater oxygen uptake (increase max )
• Partial pressure and work:
- Increase in rate of energy expenditure of skeletal muscles causes a local decrease of PO2. This will enhance arteriolar vasodilation and so increase blood flow and O2 off-loading.
- Increased energy expenditure also causes increase of temperature and PCO2 and decrease pH shifting the oxyhaemoglobin equilibrium to the right, i.e. higher partial pressure is needed to achieve same saturation.
• Diffusive capacity of lung: diffusing capacity of the lung increases by recruitment of capillaries (primarily supernumerary capillaries) to increase surface area of diffusion.
- Partial pressure of oxygen in pulmonary capillaries falls (higher oxygen uptake by peripheral tissues) while alveolar pressure remain constant. The result is a greater gradient of pressure to drive diffusion
• Erythrocyte transit time: time it takes for a red blood cell to travel through pulmonary capillaries. Loss of transit time means alveolar O2content does not equilibrate with capillary O2 content and the haemoglobin is not saturated.
- This in addition to HbO2 shift where same partial pressure only gives a lower saturation of oxygen, the arterial oxygen content is reduced
• Effect of exercise on oxyhaemoglobin equilibrium: exercise increase CO2 production hence decreased pH and increase temperature. This causes a right shift of the curve. The result is
- At PVO2 of 20 mmHg (around peripheral tissue), oxygen saturation drops from approximately 80 to 30 mmHg
- At PCO2 of 100 mmHg (around pulmonary capillary), oxygen saturation drops from 200 to 180 mmHg
- With a lower cardiac output, e.g. 24 than 32, the same oxygen uptake rate can be achieved.
- Loss of PO2 won’t make a significant different to oxygen saturation as loss of partial pressure cause only a small drop in oxygen content (occurring at the flat disproportionate segment of the graph)
• Diffusion into mitochondria: due to the right shift, at the same content, there would be a greater partial pressure present to unload the oxygen.

where PtO2 is the partial pressure of the tissue

• Capillary exchange of oxygen: peripheral passage of blood from arterial to venous end of a capillary leads to diminution of PO2 while in the pulmonary capillaries, the vice versa occurs.
- Change in partial pressure is due to length of capillaries. The shortness of pulmonary capillaries is compensated for by the density of the system.
- Capillary density can improve endurance training and diffusive transport of O2 to the mitochondria.
- Striated muscle tissue develops more capillaries with endurance training to enhance diffusive supply of oxygen. But hypertrophy of myocytes can offset this mechanism with increased diffusion distance
• Work of a breath: as power increases for a heavy exercise, oxygen consumption also increases in proportion. However power needed to work breathing is very minute and only increases slightly with heavier workload. Overall increased work leads to decrease relative respiration.
- Inspiration is active and expiration is passive so energy efficiency

Lecture 15: Lung defense mechanisms: cough and sputum

• Function of defense: to preserve sterility in the lung parenchyma, a place of favourable conditions for microbial growth, and prevent pathogenic invasion.
• Physical defense: structural and physiological mechanisms in the airway to remove particles. Large particles can respiratory symptoms.
- Upper airway filter: size-dependent filters in the nose (e.g. hairs) can remove as small as 10 µg particles (2 µg are respirable). Structures such as turbinate bones (conchae) increase surface area for filtering and particles have to pass at right angle to enter upper airways.
- Reflexes: sneezing and coughing as response to irritation of particles can clear the upper and lower respiratory tract respectively.
- Mucociliary clearance: cilia and mucus of the lung epithelial cells clear particles ranging from 5-10 µg in the upper and 2 -5 µg in the lower.
• Cellular/immunologic defense: mechanism involving host immune cells as there is an absence of muco-ciliary exhalation and cough at the periphery of the lung parenchyma (alveolus etc)
- Phagocytic: local alveolar macrophages and polymorphic neutrophils located at the wall of the capillaries sense presence of foreign pathogens (cytokine signaling IL-8). They migrate to deal with the invasion. Radical is released by the neutrophils to damage the cells etc.
- Immunologic: S.IgA
- Humoral: Other Ig, bronchial associated lymphoid tissue (similar to Peyer’s patches)
- Limitations: direct rapid stimulations such as inflammation or smoking over-recruit white blood cells causing excessive release of elastase that can break down lung tissues
• Muco-cillary clearance: a very important defense mechanism that involves secretions of mucus by the epithelial lung cells to trap particles while the coordinated beating of cilia on the luminal cells forms a “mucociliary escalator” that clears the mucus.
- As linear velocity of air down your airway drops (due to increasing cross-section area etc), particle slows to a degree where it becomes easily trapped.
- Mucus contains antimicrobial substances such as defesin and glycoproteins mucin particles, DNA and proteins. Increase in quantity of these will cause an increase in viscosity.
- Coordinated beating between cells with rapid strokes
- Mucus gland is discontinuous in the periphery to prevent excess mucus secretion and drowning of alveoli
- Pericellular fluid: fluid produced by the clara cells to hydrate the mucus layer (which lies just above it)
- Limitations: this process can not clear mucus that too thin, i.e. must wait until mucus increase in volume and viscosity to remove.
• Cough: a body reflex in which a rapid forceful expiration occurs as an attempt to clear the airways.
- Events: inspiration is immediately proceeded by a large rise in intrathoracic pressure and the glottis is pushed open. Gas flow reaches high velocity in order to remove unwanted particles or blockage.
- Stimulation: irritant receptors at the lower respiratory tract send signals through afferent fibers of 5th, 9th and 10th cranial nerve to the cough center in the medulla. Efferent fibers such as vagus, phrenic, and intercostal nerves then relay to cause intercostals and anterior abdominal muscles to contract.
- Limitations of cough: passing down the airway, the total cross-sectional area of each level increases exponentially while the linear velocity of air flow decreases. At around the 16th branch, flow velocity is so low that it is impossible to generate a sheer force
- Compromise of the cough: cough is ineffective if linear airflow is too low and this can be caused by muscle weakness or airway disease. Furthermore, if mucus is excessively sticky and thick, coughing might not be able to expel.
• Sputum: thick substances containing mucus, saliva, microbes that is coughed up from the respiratory tract and ejected by mouth. Production of sputum is always abnormal.
- Event: offending agent is diluted and entrapped within the airways. Ineffective mucocillary clearance will cause mucus to accumulate, become viscous and eventually stimulate irritant receptors leading to reflex cough
• Types of sputum:
- Mucoid: white/clear and often viscid
- Serous: clear, frothy and sometimes pink due to RBC
- Mucopurulent: yellow/green pigmented as a result of bacteria and inflammatory substances (contains WBC)
- Blood-stained sputum: red/pink
• Disease states: increased mucus production with leaky capillaries during conditions such as inflammation. Proteins leaks from serum while DNA released from neutrophils death
- Dyskinesia: congenital cilia immobility as a result of genetic defect of the dynein gene.
- Cystic fibrosis: thick mucus and recurrent infection as pathogen can not be cleared
• Manifestation of clinical case:
- Pleuritic pain of the parietal pleura (visceral have no pain sensation)
- Red blood cells in sputum
- Edema of the alveoli with inflammatory substance and cellular debris. Lung becomes less compliant and stiffer
- Mediastinum moves to the right to compensate for smaller sized lung

Lecture 20: Techniques for measuring lung function

• Three aspect of pulmonary function: testing for ventilation, gas-exchange, perfusion and respiratory control
• Obstructive lung disease: when FVC decreases more significantly than FEV
• Restrictive lung disease: when FEV decrease more significantly than FVC
• Dynamic lung volume: dividing the lung into capacity and volume.
- spirometry: method of pulmonary function test in which lung function is gauged through amount and or peed of flow generated. It measures various lung capacities and volumes during a forced expiration and forced inspiration preceded by a maximal inspiration.
- FVC: forced vital capacity is the total volume expired
- FEV1: forced expired volume in one second. Used to indicate likelihood of death with anesthesia.
• Indication of lung volumes: in general assess if respiration is impaired, i.e. constricted airway
- to establish and confirm a diagnosis of obstructive ventilatory defect
- assess effect of intervention
- preoperative evaluation when airway obstruction is present
- used for assessment of fitness to participate in various recreation or work relative activities
- assess the impact of work place explore on airway/lung function.
• Static lung volume and TLC: lung parameters that does not change, e.g. total lung capacity
- plethysmography
- helium dilution
- lung volumes by nitrogen washout
- These in conjunction with SVC can measure static volumes and capacities of the lung.
• Indications using static lung volumes:
- restrictive ventilatory defect
- differentiating types of lung processes characterized by air limitations that have similar forced expiratory configuration.
• Method of measurement:
- plethysmography: sitting a patient inside a closed containers, the pressure and the volume of the system in recorded. The patient then makes an inspiratory effort through device in which the chest volume expands decreasing the intrathoracic pressure with the mouth shutter opening. As a result the pressure within the container will change (measured as PMo) and using Boyle’s law, the new specific volume of air inside the container can be derived. Difference between the current and original will represent the change in gas at thoracic volume. When mouth shutter is closed, functional residue volume can be assessed. Initial pressure and residue volume is set, and after inspiration, the new volume is obviously the residue volume plus the change in thoracic volume measured before. Pressure can be measured at the mouth. Simple algebra can work out the answer. NOTE: panting of the patient will cause a consistent change in volume and pressure of container and this can be used to monitor airway resistance.
- helium dilution: measuring FRC and TLC by using conservation of mass (concentration and volume). The patient is situated in a chamber containing a known concentration and volume of helium. After successive deep breath, helium concentration at the mouth will fluctuate and eventually stabilized. At this point the concentration of the helium in chamber and mouth is equal and thoracic volume can be computed. This is possible as helium does not cross blood-air barrier
- Nitrogen washout: using the principle of conservation of mass, the method measures the volume of gas in the lung through expired nitrogen. The patient breathes in 100% O2 while expiring nitrogen from the lung space. After repetitive breathes, the expired N2 will eventually become zero. And so total N2 volume is the sum of all expired volume. Due to nature of emphysematous and COPD lung, this test is often impossible to perform, i.e. obstructed airways will have poor ventilation and nitrogen unable to be expelled.
• Airway resistance: there are three types of lung resistance, airway resistance, and total respiratory system airflow resistance.
- method: two manoevres are required - panting with shutter opening and panting with shutter closed. During open shutter panting, the changes in lung volume and flow are measured, immediately after the shutter is closed and change in mouth pressure and change in body plethysmograph pressure lung volume are measured.

Raw = Pressure/flow

• Indications of air resistance:
- Measurement of resistance Raw aid in the diagnosis of obstructive lung disease.
• Bronchodilator response: bronchodilators can ameliorate the effect of airway obstruction can be assessed with pulmonary function tests before and after. Some factors to consider:
- patient respond to one type of bronchodilator but not another
- variable response to same medication at different times
- beta-adrenergic aerosol: most common bronchodilator for pre and post testing. Spirometry/ plethysmography is performed after an appropriate interval and absolute and percentage change in function is calculated.

% change = (Highest Pre-Bronchodilator FEV1 – Highest Post-Bronchodilator FEV1)/Highest Pre-Bronchodilator FEV1

• Indications of bronchodilator response:
- reversibility of airway obstruction as demonstrated by a reduced FEV1/FVC ratio (increasing FVC due to bronchodilator)or other indicators of flow limitations
- evaluation of alternative drug regimens in patients
- reversal of bronchospasam induced by bronchial challenge test
- preoperative evaluation of obstruction reversibility
• Bronchoprovocation testing: evaluation of airway hyper-responsiveness such as that of asthma in patients with unclear symptoms. Pharmacological agents such as acetylcholine, metacholine, histamine are adenosine-5-monophosphate can all change FEV1 parameters of the lung allowing for diagnosis
- sensitivity: how well a test can pick up true positive
- specificity: how well a test can reject true negative
• Indication of bronchoprovocation:
- diagnosis of asthma can occasionally be difficult due to its overlap with COPD and other cause of airflow limitations such as tumours.
- does not provide 100% accuracy but some evidence for asthma
• Alveolar-capillary diffusion assessment: used to assess the condition of the alveolar air-blood interface
- single breath carbon monoxide diffusing capacity: DLCO derived from Fick’s law for carbon monoxide can be used to evaluate the state and function of the passage from distal air spaces to pulmonary capillaries. Rate of CO clearance depends on the difference in partial pressure of CO in the alveolar and capillaries. However as CO binds to haemoglobin with great avidity, partial pressure of CO in blood is approx 0 and so:

- method: breathing in a volume of test gas containing low concentration of an inert tracer gas and low concentration of CO with 21% O2 and balance N2. Test gas is held in lung for 10 seconds to maximize perfusion of lung. The gas is breathed out. Analysis of the dilution of inert gas can evaluate lung space. With this CO partial pressure at the alveolar can be worked out (diluted through the lung) and assessing CO concentration in expired air finally is used to measure flow rate
- Limitations: using a single value to assess the properties of all alveolar lung units is inaccurate but the overall CO uptake is clinically useful.
• Indication of diffusion assessment:
- evaluation and follow-up of disease which involve lung parenchyma
- emphysema
- differentiating among chronic bronchitis, emphysema (loss of surface area) and asthma (loss of airway flow)
- evaluating of pulmonary involvement in systemic diseases
- evaluation of cardiovascular disease
- predication of arterial desaturation during exercise in some patient lung disease
- quantification of impairment and disability associated with interstitial lung disease and emphysema
• Progressive Exercise Test (CPET): assessment of cardiopulmonary function during increasing exercise levels and combines the routine measurement of ECG, blood pressure, power out put with analysis of exhaled gases and arterial haemoglobin saturation.
- Method: the patient breathes into a bag while ECG devices measure heart activity
- Variables assess: oxygen, carbon dioxide, expiratory flow rates along with other cardiopulmonary variables are measured during a CPET to evaluate the physiological stress on the body.
- Uses: used when patient complains of shortness of breath, dyspnoea on exertion, exercise intolerance or for preoperative risk assessment.
• Indication of CPET:
- determination of exercise capacity
- determination of any exercise impairment
- identify abnormal response to exercise
- risk stratification and exercise response for training and rehabilitation
- evaluate health and result of treatment
- preoperative evaluation
- impairment/disability evaluation
- selection of patient for cardiac transplantation
- evaluating unexplained dyspnoea
• Maximum expiratory and inspiratory pressure
- the measurement of respiratory muscle forces, maximum inspiratory pressure (MIPS) and maximum expiratory pressure (MEPS). Assess the aggregate force of pressure that respiratory muscles can generated against an occlusion at the mouth.
- MIPS: indicate diaphragmatic strength and measured from max inspiration from RS
- MEPS: indicative of abdominal and intercostal muscle strength from max expiration from TLC
• Indication of pressure:
- quantify the degree of respiratory muscular weakness that occurs in neuromuscular disease, obstructive lung disease causing hyperinflation (e.g. emphysema).
- Diagnosis and management of a patient with actual or suspected injury to the respiratory muscles
- assessment of defect of progressive disease on respiratory muscle function
- evaluate the effectiveness of therapy designed to improve respiratory muscle strength

Lecture 23: Surfactant

• Surfactant: amphipathic substances produced by type II alveolar cells that line the squamous cells of the lung alveolar to reduce surface tension, and contribute to host defense.
• Surface features: molecules at the edge of liquid solution with different physical energy characteristics to those molecules of the bulk solution.
- Net intermolecular force: Molecules in the solutions are stabilized by bonding forces in all directions however molecules at the surface, the net force is into the solution.
- The net force is called surface free energy and is equivalent to surface tension. It favors overall collapse of the surface into the smallest area possible.
• Surface tension: this is measured by force per unit length (Nm-1)
, where γ is surface tension

• Composition of surface surfactant: 95% phospholipids, 5% proteins.
• Phospholipids: contains a hydrophobic tails that favors non-aqueous phase (i.e. air) and a hydrophilic tail head that favors aqueous phase (water). The main type of phospholipid is phosphatidylcholine (70-80%)
• Surfactant proteins: four types of proteins
- Surfactant protein A: large hydrophilic for surface tension reduction, host defense and regulation of surfactant synthesis.
- Surfactant protein B: small lipophillic for formation of tubular myelin and formation and stabilization of phospholipids monolayer
- Surfactant protein C: small lipophilic for formation and stabilization of the phospholipid monolayer
- Surfactant protein D: large hydrophilic for regulation of surfactant synthesis and host defense.
• Surfactant metabolism: type II alveolar cells produce and recycle surfactant. These are cuboidal cells situations adjacent and within the angles of alveolar spaces. They have distinctive lamellar bodies that are intracellular storage sites.
- Phospholipids synthesis: phosphatic acid is made from glycerol-3-phoshate. Polar head groups such as choline derived from the diet are combined with the acid to form phospholipids.
- Protein synthesis: all four proteins are made in alveolar type II cells while all but SPC are made in Clara cells.
• Hormonal control: in fetus, surfactant synthesis increase toward the end of gestation which coincides with maturation of pulmonary epithelial cells. This is controlled by endogenous glucocorticoids and cortisol
- Increase from thyroid hormones, beta-adrenergic agonist, estradiol, insulin
- Decrease with testosterone
• Storage and secretion: after synthesis, phospholipids are transferred from the ER to the Golgi bodies prior to produce of lamellar bodies.
- Lamellar bodies; a core of surfactant phospholipids arranged in layers with surfactant associated proteins on the periphery. Lamellar body secretion results from stimulation of beta-adrenergic receptors and this causes an increase in intracellular CAMP and cytostolic Ca2+, which causes exocytosis of lamellar bodies.
• Formation of surfactant layer: once the laemellar bodies is secreted, SPA and SPB cuase them to expand to form tubular myelin which have a fishnet appearance. Transition to the phospholipids monolayer involves actions of SPA, SPB and SPC and repeated expansion and reduction of the surface area.
- Sighing: with reduction in tidal volume, surfactant is squeezed out and thus sighing allows expansion of surface area for distribution and insertion of newly formed phospholipids to restore concentration.
• Degradation: turn over rate is between 3 to 11 hours. Large amount of pulmonary surfactant phospholipids are taken up by alveolar type II cells and recycled while the rest is transported out by the surface tension gradient toward ciliated airways and lost through EC enzymes, macrophages and epithelial absorption.
• Action of pulmonary surfactant: hydrophobic components of the surfactant are adjacent to each other at the surfaces which lowers the intermolecular attraction at the surface. Pulmonary surfactant also has the property to change surface tension with changing surface area (increase area equal increase in tension) in addition to produce hysteresis. This is important to maintain alveolar stability
• Physiology of surface tension and surfactant:
- Pulmonary surface tension:
¬ where the alveolar wall thickness can be neglected and alveolar is considered spherical
- Pulmonary surfactant reduces the tendency for large alveoli to collapse into smaller alveoli
- Law of Laplace shows as surface tension decreases, the pressure required to increase the radius of an alveolus is reduced
- Low surface tension allows alveolus to be very small without large pressure to maintain or change volume hence the alveolar capillary membrane is very thin.
• Fluid balance: alveoli surfactant reduce the tendency for fluid to be sucked into the airspace
• Defense: a surface tension gradient exists between alveoli and ciliated airways and this facilitates a net flow of surface toward ciliated airways. Particulate matter trapped in this layer is conveyed to these regions and expelled by the lung.
- SP-A and SP-D act to bind to pathogens to promote action of macrophages
• Other functions of surfactant:
- Reduction of adhesion
- Aids in hydration and rheology mucus
- Reduces the formation and maintenance of liquid plugs.

Lecture 24: Control of Breathing

• Important of respiratory control to exercise:
- Match volume of exhalation to volume of O2 inspired
- Protect alveolar partial pressure of oxygen and carbon dioxide
- Protect arterial O2 by minimizing A-aDO2
- Minimise work of respiratory muscles
• Feedback loop:
- Changes in gas exchange and blood gas levels are perceived as afferent input by chemoreceptors (arterial blood), lung receptors (mechanics) and high CNS center.
- Pacemakers in central integration areas such as pons and medulla respond to these stimuli
- Nerve efferent is sent out to ventilatory muscles and secretory gland to modulate behavior etc
• Central rhythm generator: a constant tonic input (above oscillatory threshold) is required to maintain rhythm generation. This is stimulated by
- Hypercapnic drive
- Hypoxic drive
- Wakefulness input
- Exercise
• Inspiration cycle: during inspiration, activity of inspiratory neuron increase steadily from a positive feedback and at the end, the system shut of rapidly and expiration takes place with recoil of lung.
• Central controllers:
- Medullary respiratory center: this is the rhythm generator made up of dorsal respiratory group (inspiration), ventral respiratory group (expiration only active in hyperventilation) and pre-botzinger complex (basic generator)
- Poutine respiratory center: consists of 3 nucleii. Apneustic center (upper pons and an inspiratory center) and pneumotaxic center (switches off inspiration and signals expiratory neuron)
• Sensors:
- Central chemoreceptors: located near the ventral surface of the medulla and responds to changes in CO2 indirectly via effects on H+ ion concentration of CSF. Chronic hypercapnia causes adaptation due to transport of bicarbonate across blood-brain barrier
- Peripheral chemoreceptors: these consists of all the hypoxic drives and 20% of hypercapnic. Aortic bodies located over the aortic arch and senses O2 content as well as pO2 (able to react to anaemia). Efferent is transmitted via the vagus. Carotid bodies on the other hand locate at the bifurcation of the common carotids and senses pCO2 and pH in addition to pO2. Extremely high blood flow keeps pO2 near arterial level. For both, simultaneous changes in partial pressure levels can augment effect.
• Lung receptors:
- Irritant receptors: rapidly adapting receptors located near carina and large bronchi. It’s responsible for irritant reflexes such as coughing, mucus production and tachypnea. Stimulated by noxious particles, dust and mechanical stimuli
- Stretch receptors: slow adapting receptors located in smooth muscle of bronchi and trachea. These are presume to be responsible for early termination of inspiration by increase lung volumes, i.e. stretch (exceed 800-1000mL)
- C/J-receptors: makes up the majority of afferent fibers. C receptors are located in bronchial interstitium. These are excited by both chemical and mechanical stimuli, e.g. histamine, bradykinin and vascular distension and causes rapid shallow breathing, bronchoconstriction and mucus production.
• Other receptors: nose and upper airway, joint and muscle, gamma system and arterial baroreceptors
• Response to CO2:
- Linear response
- Increase by hypoxia due to peripheral chemo-receptor
- Varies with age, height and sex
• Response to O2
- Hyperbolic response
- Less response than pCO2
- Important in patients with severe lung disease or normal subjects at altitudes
• Response to pH:
- Mainly due to peripheral chemoreceptor stimulation but central effects as well
- Less response than to iso-pH change with CO2, i.e. CO2 decrease will lower central chemoreceptor output
- Acidosis increase CO¬2 sensitivity
• Response to exercise:
- Ventilation increase promptly to high levels
- Partial pressure of O2, CO2 and pH remain normal
• Ventilatory adaption:
- In chronic hypercapnia (COPD), renal secretion of bicarbonate leads to correction of pH and CO2 drive is down regulated. Removal of hypoxic drive with O2 administration can lead to decrease in respiratory drive and CO2 narcosis. Also saturation of Hb with O¬2 means CO2 will be dumped into plasma but down-regulated response cause CO2 to not be expelled.

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