Surfactant and Resistance - Respiratory System PDF

Surfactant and resistance 12 February 2025 11:39 The distending pressure is generated by the elastic recoil forces of the lungs and chest wall, and compliance determines volume for any given distending pressure. But what sets compliance? Chest wall compliance This depends on the rigidity of the th...

Surfactant and resistance 12 February 2025 11:39 The distending pressure is generated by the elastic recoil forces of the lungs and chest wall, and compliance determines volume for any given distending pressure. But what sets compliance? Chest wall compliance This depends on the rigidity of the thoracic cage and on its shape. Changes in rigidity or shape will change chest wall compliance. In cases of arthritic spondylitis or kyphoscoliosis the chest wall changes shape and compliance decreases, increasing the work of breathing. There are no diseases associated with an increase in chest wall compliance. Lung compliance The elastic properties/compliance of the lung are determined by several variables An obvious one is the inherent elastic properties of the lung tissues (e.g. collagen, elastic fibres). It is when these reach their elastic limit at higher lung volumes, that the compliance curve flattens out However compliance is also determined by surface tension forces which arise due to the air-liquid interface. The air-liquid interface only exists in lungs filled with air, not with fluid. If a lung were to be filled with fluid, there would be no surface tension as there is no air-liquid interface, this causes the compliance to be much higher. Surface tension is a collapsing force that must be overcome when the lungs are inflated, in air-filled lungs, more work must be done to stretch the lungs against surface tension, much more work than is needed to stretch the lung tissue. 2/3 of the elastic recoil is due to surface tension Surface tension This can be thought of as a skin on the surface of the water where it meets air, it arises from the water molecules attraction to one another and being held together, on the surface there are no water molecules above, so the net attraction is inwards, forming tension on the surface. Lung alveoli are essentially fluid lined spherical bubbles. The fluid creates tension (T) from a tangential component of force, creating an inwards collapsing force. The collapsing force also generates an outward pressure, which counteracts the tension in the wall. The bubble has a certain diameter where it reaches a point where the internal collapsing force is equal to the force from the internal pressure generated by the gas phase. Laplace's Law (for spherical vessels) Tension is constant, as r decreases, the pressure must increase to counteract that to keep them inflated. Smaller bubbles must have a greater internal pressure to keep them inflated. This can lead to a misconception about how different sized alveoli co-exist. Within the lung it should not be a consideration in how they co-exist Alveolar inter-dependence is the concept that alveoli co-exist as they are bounded by other alveoli, the tendency for one to collapse is prevented by the tendency of others not to collapse. The spheres of the lungs should be thought of as a foam, not like a bunch of grapes. Calculations using a simple air-interstitial fluid interface in the lungs shows a very high surface-tension, reducing compliance significantly, such that breathing would be almost impossible. But breathing is very much possible. This shows there is not a simple air- interstitial fluid lining, there must be something other than interstitial fluid to decrease compliance, this is the purpose of surfactant Surfactant Surfactant is a surface acting substance. It is made up of phospholipids, cholesterols and proteins. It is essentially a detergent that greatly lowers surface tension in alveoli The surface tension of pure interstitial fluid is 70mN/m, with surfactant it can drop lower than 2mN/m. The main component responsible for this effect is DPPC (dipalmitoyl phosphatidylcholine) Secreted by alveolar Type II cells Surfactant consists of a glycerol backbone, with phosphate and choline residues on one side, and palmitate residues on the other  Palmitate is hydrophobic, it sticks out the water when surfactant is placed in liquid The phosphate and choline residues are hydrophilic, so lie within the liquid Therefore due to the presence of both hydrophilic and hydrophobic ends on the glycerol backbone, surfactant lines the air-liquid interface. This prevents surface tension by preventing water molecules from getting to the air-liquid interface The detergent effect reduces alveolar surface tension, this increases lung compliance, reducing work of breathing. Post-lavage air inflation on the graph below is where the surfactant has been washed away Unlike detergents, surfactants can alter their surface tension lowering effect depending on the surface area. In alveoli with smaller radii (lower surface area), surfactants cause a greater decrease in surface tension. The DPPC is more dense, causing a greater surface tension lowering effect. Some incorrect textbooks will use this to describe how different sized alveoli co-exist, however it is via the mechanism mentioned earlier Lung compliance and disease Lung compliance can increase and decrease due to disease. Diseases such as emphysema can cause an increase in compliance Diseases such as pulmonary fibrosis or congestion can cause a decrease in compliance. Both changes make it more difficult to breathe. Infant respiratory distress syndrome (RDS) (high yield) This is one of the most common causes of reduced lung compliance. The Foetus has no air- liquid interface as all oxygen is received from the mother via the placenta and so surfactant is not needed. It only appears late in gestation (25 weeks) and doesn't reach high concentrations until around 32-36 weeks. At this point it lines the alveolar surface in preparation for air breathing. RDS is where infants are born with a lack of surfactant which can be due to a number of reasons: Maternal diabetes mellitus Prematurity These cause the lungs to have a low compliance (10x stiffer), and can also cause smaller alveoli to collapse. A fibrinous membrane (hyaline membrane) may also form on the alveolar membranes, hindering diffusion. Infants must expend a lot of energy to inflate lungs, and the lungs also deflate quickly. This can lead to infants becoming: Hypoxic – insufficient oxygen levels Hypercapnic – high levels of CO2 in blood Acidotic – too much acid in the body fluids Exhausted Lung maturity can be assessed prenatally by conducting an assay for phosphatidylcholines in amniotic fluid. This is done in all elective inductions and Caesareans to assess lung maturity before going ahead with the procedure (we might choose to delay the birth if surfactant levels are low) If the lungs are immature, we can accelerate maturation by administering glucocorticoids. However, if infants develop RDS after birth, it is still possible to instil surfactant into the trachea Adult respiratory distress syndrome (ARDS) As opposed to inherently low surfactant levels, ARDS is associated with a large number of disorders such as pneumonia, sepsis and smoke inhalation These cause damage to the alveolar-capillary interface as well as alveolar type II cells, leading to a loss in ability to produce surfactant The symptoms are similar to those present in infant respiratory distress syndrome Respiratory dynamics The work of breathing requires the movement of air. We have considered respiratory statics already (compliance), but airflow means we must also consider respiratory dynamics and resistance. Airflow resistance is defined as the pressure difference required for any given flow. The lower the resistance, the lower the pressure difference required for a given flow. Normal -1 airflow resistance is relatively low at 0.2 kPaLs. Increased resistance to breathing is the most frequent cause of ventilatory impairment. Asthma is the most common cause. The pressure difference is the difference between alveolar and barometric pressures. During a static measurement, the work required to stretch the lung is the only factor causing increases in lung volume (the patient is told to hold their breath at a certain volume such that there is no air movement). However during a dynamic measurement, we can see that more work is required to increase lung volume. This is due to dynamic resistance which occurs due to the movement of air in this measurement that must be overcome. The work of breathing has two components resistance and compliance Resistance has two components. Most of the resistance to flow is by friction in the airways - airway resistance (80-90%), there is also resistance by lung tissue friction - viscous resistance (10-20%) The flow for a change in pressure is dependent on resistance Poiseuille's equation allows us to calculate airflow resistance within airways: As the number 8, the length (L) and the viscosity are constant, we can simplify this equation to that in red. So doubling radius would decrease resistance by a factor of 16. Going purely off the first graph, the trachea would have a much lower resistance than a single respiratory bronchiole due to it having a much larger cross-sectional area However, the total cross-sectional area of the respiratory bronchioles is greater than that of the trachea and hence we can conclude that later respiratory generations have a much lower resistance than earlier generations This also means blockages in later generation airways will have less of an effect upon airway resistance than blocks in earlier generation airways Airway resistance Upper airway resistance The most common cause of airway resistance in the upper airways is intraluminal airway obstruction. This occurs upon aspiration of foreign material (especially in children) or regurgitation of gastric contents or blood Coughing tends to clear this obstruction and people should be encouraged to cough when choking. If coughing is ineffective in removing the obstruction, bronchoscopic removal may be required (if you have a bronchoscope on hand) or more commonly the Heimlich manoeuvre. This manoeuvre involves forcing the diaphragm upwards in sudden, sharp movements. It can clear the obstruction by producing a sudden increase in airway pressure distal to the obstruction. If this doesn’t work you may need to begin CPR. Increased upper airway resistance can also be caused by bronchospasm, mucus secretion and oedema, as well as severe obstruction due to the tongue falling back when unconscious. However, the recovery position prevents the tongue from doing this Lower airway resistance Lower airway resistance only accounts for around 20% of airway resistance but is still important for many reasons. Lower airways are a prime target for COPD. This can progress to a profound stage before being diagnosed as it can progress via a silent zone, where the patient is not aware that they have a resistance issue Physiological control of bronchial diameter Smooth muscle in airways is under control of the autonomic nervous system. Bronchial diameter is therefore not under conscious control. Bronchoconstriction can be caused by: Increased vagal parasympathetic activity (30% tone at rest). This also induces mucus secretion. Local chemical mediators such as histamines and leukotrienes. These may be released in response to inflammatory or infectious diseases Decreased airway CO2. This may occur due to hyperventilating Bronchodilation can be caused by: Activation of B2-adrenoceptors by adrenaline or sympathomimetics Non-adrenergic, non-cholinergic (NANC) innervation. Alveolar Gases and Diffusion 25 February 2025 11:34 Written by Walid Jamal Partial pressures in the respiratory system Inspired air Normally, air which we breathe in has the following partial pressures of oxygen and CO2. Pi O2 = 20 kPa Pi CO2 = 0 kPa Note that the partial pressure of CO2 in inspired/atmospheric air is very low and can be considered to be negligible in this case. Pi means partial pressure in inspired air. Conducting zone Partial pressures of O2 and CO2 in the conducting zone are different during inspiration and expiration. As expected, PO2 is lower during expiration, while PCO2 is greater. During inspiration: ○ PO2 = 20 kPa ○ PCO2 = 0 kPa ○ These are essentially the same pressures as inspired air. During expiration: ○ PO2 = 13 kPa ○ PCO2 = 5 kPa  ○ Note how the pressure of oxygen decreased, while the pressure of carbon dioxide increased. Alveolar space The alveolar space is different to the conducting zone in that the pressures of O2 and CO2 remain constant during inspiration and expiration. This is because the alveolar space itself has a very large volume (total volume = 2500mL). Each breath brings in about 350mL of fresh air, this is only a small volume relative to the total volume of the alveolar space. Additionally, this fresh air mixes with the alveolar air only via diffusion (unlike conducting zone where there is mass flow of air). Therefore, pressures of O2 and CO2 remain relatively stable during inspiration and expiration. Pressures in the alveolar space are: PA O2 = 13 kPa PA CO2 = 5 kPa Pulmonary blood vessels Blood arriving to the alveoli via pulmonary artery branches has a lower O2 pressure and a higher CO2 pressure than the alveoli. This allows gaseous exchange between the alveoli and the blood down pressure gradients Despite coming from a pulmonary artery, deoxygenated blood reaching the alveoli is referred to as venous blood. The actual pressures of gases in venous blood varies depending on metabolic rate, but it can be around: Pv O2 = 5 kPa Pv CO2 = 6 kPa This blood then undergoes gas exchange withart the alveoli, causing it to stabilise to alveolar gas pressures. Therefore, arterial blood leaving the alveoli has pressures of: Pa O2 = 13 kPa Pa CO2 = 5 kPa Note the use of a small ‘a’ for arterial pressures, and a big ‘A’ for alveolar pressures Due to the stable nature of alveolar gas pressures, arterial pressures leaving the lungs are relatively stable as well. Factors influencing alveolar gas pressures Factors influencing PA CO2 While alveolar gas pressures are stable between inspiration and expiration, they can be varied by changes in alveolar ventilation and metabolic rate  Alveolar ventilation – Increasing alveolar ventilation decreases PA CO2, and vice versa. Therefore, PA CO2 is inversely proportional to alveolar ventilation, V̇A. Metabolic rate (VCO2) – Increasing VCO2 increases PA CO2, they are therefore proportional. These two relationships can be combined as such: A constant can be used to turn this into an equation: This equation can be used to estimate alveolar pressure of CO2 at different metabolic rates and alveolar ventilations. This can be represented graphically: This graph applies for a particular constant VCO2 (metabolic rate), in the case of the above graph this is the metabolic rate at rest. This yields an alveolar PA CO2 of 5 kPa at a normal -1 ventilation of 5 Lmin. Increasing ventilation beyond the body’s requirements (hyperventilation) will decrease PA CO2, while decreasing ventilation (hypoventilation) will drastically increase PA CO2. During physical activity, VCO2 increases. The hyperbola is shifted upwards. In this example, VCO2 has doubled. According to the equation: V̇A must increase by the same factor (2x) in order to keep the PA CO2 at 5 kPa. This is shown on the graph By keeping PA CO2 constant at 5 kPa, Pa CO2 (arterial) also remains at 5 kPa. Therefore, by measuring Pa CO2, the adequacy of alveolar ventilation (V̇A) can be clinically evaluated. If Pa CO2 is too high, then alveolar ventilation is insufficient to match the body’s demands. Factors influencing PA O2 The same 2 factors above also influence alveolar pressure of O2, but in the opposite direction. Increasing alveolar ventilation (V̇A) increases PA O2. Increasing metabolic rate (VO2) decreases PA O2. This relationship can be applied to the following equation: Note that, in this case, we are subtracting from the PO2 of inspired air (Pi O2), which is not negligible for oxygen, and normally has a value of around 20 kPa. The alveolar gas equation (AGE) This equation is derived from the combination of the equations for PA CO2 and PA O2, and substituting using the formula for RQ: RQ = VCO2/VO2 --> VO2 = VCO2/RQ And therefore: Pi O2 is easily estimated, this is always used for dry air at 37°C to allow comparison of measurements. Pi O2 = (PB – PH2O) x FiO2 = 19.68 kPa at sea level Where PB is barometric pressure, PH2O is water vapour pressure, and FiO2 is fractional concentration of oxygen in the air (0.21). R (or RQ) is assumed to be 0.8 in a normal diet. PA CO2 is assumed to be equal to Pa CO2 (arterial), which can be measured from a blood sample. Given these 3 values, it is possible to calculate the alveolar PA O2. This is then compared to the arterial Pa O2 from a blood sample, this is known as the A-a gradient. Normally, the measured Pa O2 value is 1kPa lower than the estimated PA O2 value. However, if the difference is greater than 1 (A-a gradient elevated) then there is an impairment in diffusion across the alveolar-capillary membrane, or alveolar  perfusion. This could, for example, be caused by interstitial lung disease causing fibrosis. If there is an issue with alveolar ventilation, for example hypoventilation, both PA O2 AND Pa O2 would be reduced together, therefore the A-a gradient would be normal. A normal A-a gradient and an increased Pa CO2 indicate that there is hypoventilation. Movement of gases across the lungs For O2 and CO2 to be exchanged between the alveoli and the blood plasma, they must pass through 3 layers: Alveolar epithelium Basal lamina (basement membrane) Capillary endothelium This is a relatively thin alveolar-capillary membrane Both gases diffuse via a gaseous phase and a liquid phase. Gaseous phase Diffusion rate in the gaseous phase depends on the pressure gradient of the gas, as well as its molecular weight (MW). Diffusion rate is inversely proportional with √MW ;this is Graham’s Law. MW CO2 = 44 MW O2 = 32 Therefore, in the gaseous phase, oxygen diffuses faster. CO2 diffusion in the gaseous phase is 0.85x the speed of O2 Liquid phase Diffusion rate in the liquid phase is dependent on the concentration difference in solution. Concentration of the gas depends on its partial pressure and solubility; a more soluble gas will diffuse faster in this state. This is Henry’s law: Concentration of gas = partial pressure x solubility coefficient (α) -1 -1 α CO2 = 5.30 ml L kPa -1 -1 α O2 = 0.23 ml L kPa This means that CO2 is more soluble than O2. Based on this, CO2 diffuses 23x faster than O2 in the liquid phase. Diffusibility ratio of CO2/O2 This is the measure of the overall diffusion rate ratio in both phases between the two gases. It can simply by calculated by multiplying the ratios of each phase: 0.85 x 23 = 20 Therefore, CO2 diffuses 20x faster than O2 overall. This is despite the fact that O2 has a greater pressure difference between alveoli and blood (8 kPa difference) compared to CO2 (1 kPa difference). This means that any impairment in gaseous diffusion will affect O2 diffusion first. Therefore, hypoxia (insufficient O2) usually presents as a symptom before hypercapnia (too much CO2). Uptake of O2 across the alveolar-capillary membrane The uptake of gas into blood depends on the solubility of the gas, and whether it chemically combines with other molecules (e.g. haemoglobin). Blood in a pulmonary capillary has a transit time of around 0.75s, this is the amount of time during which blood is at an alveolus and able to exchange gas. Before discussing oxygen, we will use two different gases simply as an example, to show two different uptake patterns. Diffusion-limited gases Carbon monoxide (CO) is a gas with a very high solubility, and a very high affinity to haemoglobin (therefore high chemical combination). Assuming that it has an alveolar pressure (PA) of 13 kPa similar to oxygen, its uptake will follow this shape on a graph: Pgas in this graph refers to the pressure of the gas in the blood. Due to its high solubility and high chemical binding properties, the pressure of the gas (in gaseous state) rises very little during its transit time. This means that, even at the end of the transit time, CO fails to achieve equilibration with the alveolar pressure of 13 kPa. This means that CO is considered a diffusion-limited gas. The only way to increase partial pressure of a diffusion-limited gas such as CO is by increasing the alveolar pressure, to increase the rate of uptake (increase gradient of graph). Increasing the speed of blood flow to the alveoli will not increase uptake (nor partial pressure) in this case. Perfusion-limited gases On the other end of the spectrum, N2O is a gas with very low solubility and relatively no chemical combination. Therefore, it equilibrates rapidly with alveolar pressure long before the transit time is over, leaving a large amount of time through which there is no net diffusion. The spare time left over is known as the diffusion reserve. By increasing the speed of blood flow to the alveoli (increasing cardiac output), the transit time is cut short, and therefore the diffusion reserve can be used by new blood from the heart, to take up even more gas. Therefore, to increase gas uptake for such a gas, blood flow must be increased. N2O is therefore a perfusion-limited gas. Oxygen is also a perfusion-limited gas. It has a relatively low solubility. It equilibrates more slowly than N2O because it does have a level of chemical binding with haemoglobin. Nonetheless, it still has a very high diffusion reserve of around 0.5s. This explains why, when the body needs more oxygen for example due to exercise, cardiac output is increased. This increases blood flow and allows blood to make use of the diffusion reserve of oxygen by reducing transit time, for example to 0.5s. This allows even more oxygen to be taken up by the blood. Uptake abnormalities Some disorders, such as pulmonary oedema or thickening of the alveolar capillary membrane, reduce the diffusion capacity of the lungs and the rate of oxygen uptake. This could mean that a person has a diminished diffusion reserve, taking longer time to achieve equilibration. In such an individual, increasing blood flow during exercise (reduced transit time) would not be beneficial as there is no diffusion reserve to take advantage of, and they may experience hypoxia during exercise, especially at high altitudes where alveolar oxygen pressure is reduced. In severe diffusion abnormality, oxygen uptake follows a diffusion-limited pattern. Even with a full transit time, arterial pressure is unable to equilibrise to alveolar pressure. Such a person would be breathless and hypoxic, even at rest. In order to increase oxygen uptake, alveolar oxygen pressure needs to be increased, for example by an oxygen mask. Pulmonary diffusing capacity (aka transfer factor) Flow of a gas (V̇) across a diffusion barrier is proportional to the following factors: Diffusibility (d) of gas Area of barrier (A) 1/Thickness of barrier (1/T) Pressure difference across barrier (ΔP = PA – Pcap) This is represented via the following equation: Typical values for adult lungs are: 2 Area = 85m  -6 Thickness = 0.2μm (0.2x10 m) The high area and very small thickness give healthy lungs a high diffusing capacity and high flow across the diffusion barrier. The graph on the right shows the average diffusing capacities of lungs of different organisms. There is an almost linear correlation between body mass and diffusing capacity. Also, there is a strong relationship between VO2 max and diffusing capacity. This means that our maximal oxygen consumption is limited by our pulmonary diffusing capacity. Measuring pulmonary diffusing capacity In clinical practice, it is difficult to measure diffusibility, area, and thickness directly. Therefore, the 3 values are assumed to be constant and are combined to give the diffusion constant, DL such that: DL = (d x A)/T and so, -1 -1 DL = V̇/(PA-Pcap) or DL = V̇/(P1-P2) ml min kPa It is difficult to directly measure diffusing capacity for O2, this is because Pcap (or P2) for O2 varies greatly along the capillary (between 5 to 13kPa). Instead, carbon monoxide (CO) is used, because it has a very high affinity for haemoglobin, meaning that its Pcap is effectively 0 (it is all chemically bound). Therefore, the equation becomes simplified as: DL CO = V̇CO/PA CO Once this value is obtained, it can be converted to DL O2 by multiplying by a conversion factor of 1.25. -1 -1 -1 A typical DL CO is 175 ml min kPa , this can be converted to a DL O2 of 220 ml min -1 kPa. Factors which can increase DL O2 Increased body size Pulmonary Haemorrhage Asthma - moderate to severe Exercise Lying down Factors which can decrease DL O2 A decrease in measured DL O2 can be caused by a range of pathologies: Reduced diffusion surface area ○ Loss of lung tissue ○ Airway obstruction ○ Capillary obstruction ○ Ventilation-perfusion mismatch Increased diffusion distance ○ Thickened alveolar-capillary membrane (e.g. due to fibrosis) ○ Accumulation of lung fluid (pulmonary oedema) ○ Increased intracapillary distance (e.g. anaemia leading to low Hb levels) Patients with a reduced pulmonary diffusing capacity (DL CO) share a common presentation of hypoxia and cyanosis which are made worse by exercise. Due to their hypoxia, they have an increased alveolar ventilation due to increased work of breathing to try and recover, causing a reduction in Pa CO2. They would have a normal ventilatory capacity. The DL CO test cannot differentiate between the different causes/aetiologies, therefore cannot be used on its own to make a diagnosis. It can only identify that there is something wrong. After identification of an abnormality, further tests and history taking are required to reach a diagnosis. Ventilation and Perfusion 04 March 2025 11:00 The A-a PO2 gradient This is the natural difference in PO2 of alveoli and that of arteries. Such a gradient does not exist for PCO2, due to the high diffusibility of CO2. The alveolar partial pressure, PAO2 is around 13 kPa. Blood arriving to the lungs via a pulmonary artery, and then a pulmonary capillary, has a lower PO2 of around 5kPa. As the blood passes through the pulmonary capillary, it equilibrates with the alveolar PO2. Thus, blood leaving the pulmonary capillary has a PaO2 of around 13 kPa as well. This blood returns to the heart. However, the oxygenated blood being pumped out the heart via the aorta has a reduced PaO2 of 12 kPa. Therefore, there is a difference of 1 kPa between the two partial pressures. This is a healthy A-a gradient. There are 2 reasons for this difference:  Shunts – This refers to blood returning to the left side of the heart before it can be oxygenated by the lungs. This mixes with the oxygenated blood from healthy pulmonary capillaries, reducing total PaO2. Ventilation/perfusion (V/Q) mismatch – At rest, the lungs receive a pulmonary ventilation (V̇) of 4 L/min. Cardiac output to the lungs provides a blood flow (Q̇) of 5 L/min. Therefore, there is a natural 0.8 V/Q ratio. This means that the lungs are not able to oxygenate all the blood it is receiving, due to limitations of ventilation. This V/Q ratio varies throughout lung tissue, it is not constant all around the lung. These two factors contribute to a natural A-a gradient of around 1 kPa. Increasing the effect of either factor will lead to an increase in the A-a gradient, and a fall in PaO2 leading to hypoxia. This A-a gradient increases naturally with increasing age, due to increase in the V/Q mismatch. In order to predict someone’s A-a gradient, we divide their age by 30 and add 0.3. Right-Left (R-L) Shunting As mentioned above, right-left (R-L) shunting refers to where deoxygenated blood mixes in the left ventricle with the oxygenated blood, before being pumped out into the systemic circulation. This mixing reduces the PaO2 of blood, contributing in part to the A-a gradient. There are natural R-L shunts which are part of normal, healthy anatomy. Additionally, further R-L shunts may arise from certain pathologies. Natural R-L shunts These normally affect only a small part of the cardiac output (1-2%), and therefore do not impair gaseous exchange significantly. Thebesian veins – These are small venous channels which drain the capillaries of the heart wall itself. These veins drain deoxygenated blood directly into the chambers  of the heart. This deoxygenated blood mixes with oxygenated blood in the left ventricle. Bronchial circulation – From the thoracic aorta, arterial branches supply oxygenated blood to the bronchi and bronchioles. This becomes deoxygenated by tissue metabolism and does not become oxygenated as gas exchange does not happen in these bronchi and bronchioles. The deoxygenated blood from bronchopulmonary veins then drains into the pulmonary vein returning to the left side of the heart. Therefore, deoxygenated blood is mixing with oxygenated blood in the left ventricle. These anatomical shunts receive no ventilation, therefore they can be referred to as having a V/Q ratio of 0. Pathological R-L shunts This is where blood reaching alveoli through some pulmonary capillaries does not get oxygenated due to a pathology. Any increase in the degree of shunt leads to an increase in the A-a difference and hence increasing deoxygenation of arterial blood. R-L shunting may occur in pulmonary disease: Airway block (e.g. foreign object or mucus) – This leads to reduced/no ventilation downstream of the blockage. Therefore, affected alveoli will not be able to transfer oxygen to the blood. The affected pulmonary capillaries therefore will contain deoxygenated blood, forming extra R-L shunts. Collapsed bronchioles or alveoli – This impairs gaseous exchange in the affected pulmonary capillaries, contributing further to R-L shunting. L-R shunts (cardiovascular shunts) These are anatomical abnormalities (as opposed to functional abnormalities such as airway block) where oxygenated blood from the left side of the heart mixes with deoxygenated blood from the right side of the heart. Consequences of this are not mainly concerning PaO2. Because of an opening allowing communication between pulmonary and systemic circulations, blood from the higher-pressure systemic circulation (left atrium/ventricle/aorta) will leak into the lower pressure pulmonary circulation (right atrium/ventricle/pulmonary artery). Increased blood flow in the pulmonary circulation can lead to congestion and pulmonary hypertension. L-R shunts can be in the form of different congenital defects: Atrial or ventricular septal defect – Incomplete closure of the atrial or ventricular septa allows blood from the left and right sides of the heart to mix. Blood will flow from the higher-pressure left side to the right side. Patent ductus arteriosus – In the developing fetus, the lungs are still not being used for gas exchange (placenta used, breathing not possible yet). Therefore, in the fetal circulatory system, not all the blood being pumped out to the lungs via the  pulmonary artery will reach the lungs. Some is able to drain into the aorta via a connection – the ductus arteriosus. This ductus arteriosus normally closes after birth. However, in some cases it does not. In this case, oxygenated blood from the higher pressure aorta will drain into, and mix with, deoxygenated blood from the pulmonary artery, instead of reaching systemic circulation. Distribution of ventilation (V̇) throughout the lung Throughout lung tissue, V/Q varies, as both ventilation and perfusion vary for different parts of the lungs. The bases of the lungs receive more ventilation than the apexes. Variation in ventilation is caused by gravity and compliance Due to gravity, the apex of each lung is retracted from the chest wall to a greater degree than the bases. The apexes are being pulled away from the chest wall by gravity pulling them downwards, this gravitational force is caused by the entire mass of the lung. In contrast, the bases are almost being pushed towards the chest wall, therefore the bases are significantly less retracted from the chest wall. The increased retraction of the apexes from the chest wall creates a more negative intrapleural pressure between the two pleural membranes, in the apexes compared to the bases. The more negative the intrapleural pressure is, the greater the volume of the lung tissue. Therefore, at FRC, the apexes have a greater volume than the bases. The alveoli of the apexes are more inflated than the alveoli of the bases at FRC. At greater degrees of inflation, lung tissue has less compliance. Therefore, the apexes have a lower compliance than the bases. This means that, when breathing in, the same change in distending pressure/pleural pressure yields a greater change in volume for the bases than the apexes. This means that more inhaled air moves to the bases rather than the apexes. Normally, to inhale 1 L of air, the pleural pressure needs to be reduced by around 0.3 kPa. By decreasing the pressure by 0.3 kPa, the volume of the bases increases more than the volume of the apexes, which are already nearing their elastic limit. This means that the bases have a greater airflow (V̇) when breathing, and therefore they have a greater ventilation than the apexes. The bases receive approximately 2.5x more of the total alveolar ventilation (V̇A) than the apexes. (Resting V̇A approximately = 4L/min) In summary, the bases have more ventilation than the apexes. Distribution of perfusion (Q̇) throughout the lung Blood flow or perfusion (Q̇) can be measured by intravenous administration of a radioactive 133 material, for example Xe , and then using radiation counters to calculate blood flow to different parts of the lungs. At rest, total perfusion of the lungs is 5 litres/min. Similar to ventilation, the bases receive more perfusion than the apexes. Of the resting perfusion, 6x more is received by the bases than the apexes. This variation is again caused by gravity. Arterial pressure (Pa) Blood arriving at the lungs through the pulmonary artery first leaves the heart through the tricuspid valve. At the level of the tricuspid valve, blood has a pressure of approximately 20 cmH2O. This is relatively low compared to the pressure of the systemic circulation. Moving vertically upwards, the blood loses this pressure. Pressure decreases by approximately 1 cmH2O for every cm moved upwards. Therefore, the blood loses approximately all its pressure 20cm above the level of the tricuspid valve (effectively 0 at this point). Moving downwards, blood pressure increases by the same rate. Therefore, the blood arriving to the bases of the lungs is at a higher pressure (Pa is higher) than that of the vertical level of the tricuspid valve. Blood arriving to the apexes of the lungs has a reduced Pa relative to the tricuspid valve. Venous pressure (PV) As blood moves from the artery to the pulmonary capillaries, and then to the pulmonary veins, pressure drops. Therefore, venous pressure (PV) at any vertical level is lower than Pa of the artery from which the blood originated, at the same vertical level. The difference between Pa and PV at the same vertical level remains constant, this is the driving force, and is approximately 10 cmH2O. At higher regions of the lungs, PV is negative. Alveolar pressure (PA) Alveolar pressure remains approximately equal to 0 cmH2O in all regions of the lungs. Perfusion zones: These changes of the 3 pressures leads to a distinct pattern, where the lung tissue can be divided into 3 zones (vertically from upwards to downwards):  Zone 1 – Alveolar pressure > arterial > venous (PA>Pa>PV). This zone does not exist in normal physiology, as it would require an arterial pressure below 0. It may arise in certain disorders, as discussed below. In this zone, there is no blood flow due to the alveolar pressure being greater than arterial, resulting in collapsed arterioles. Zone 2 – Arterial pressure > alveolar > venous (Pa>PA>PV). Here, there is a sub- zero venous pressure. In this zone, flow is dependent on the difference between arterial and alveolar pressures (Pa-PA). Therefore, blood flow increases moving vertically downwards, as Pa increases. Zone 3 – Arterial pressure > venous > alveolar (Pa>PV>PA). This zone has the greatest blood flow. Alveolar pressure is irrelevant in this zone. Explaining changes in blood flow in zone 2 In zone 2, the blood flow significantly increases moving vertically down the lungs. As the Pa increases, the Pa-PA difference increases. Also, the increased arterial pressure leads to the opening of arterioles which were otherwise collapsed. This is known as recruitment of arterioles, and increases moving vertically downwards. Explaining change in blood flow in zone 3 Blood flow in zone 3 relies on the Pa-PV difference, which remains relatively constant. However, moving vertically down the lungs, arterial pressure is increasing. No recruitment occurs here as pressure is already high enough for all arterioles to be open. Rather, increased arterial pressure moving downwards leads to distension of the blood vessels, and therefore blood flow slightly increases moving downwards. The effect of distension is less significant than recruitment. Hence, blood flow does not increase much in this zone. Pathology and Zone 1 Zone 1 does not normally exist in normal physiology, because the height of the lungs above the tricuspid valve does not normally exceed 20cm. However, zone 1 may arise in tissue which normally falls in zone 2, due to some pathology. This could be due to either: Decrease in Pa (arterial pressure) – for example due to haemorrhage. Increase in PA (alveolar pressure) – for example during positive pressure ventilation. If either, or both, of these happens, then there will be no blood flow to the apex of the lungs, because Pa is now lower than PA. The ventilation/perfusion (V̇/Q̇) ratio Variation of V/Q within lung tissue As mentioned above, the base of the lungs receives 2.5x more ventilation than the apex. The base of the lungs also receives 6x more perfusion than the apex. Both ventilation and perfusion decrease moving vertically upwards from the base to the apex. In the lower portions of lung tissue, Q > V, and therefore the V/Q < 1. Perfusion falls at a higher rate than ventilation moving vertically upwards. Therefore, V/Q begins to increase as Q gets smaller relative to V. V/Q is lowest at the base of the lungs (V/Q = 0.6).  There comes a point somewhere within the lung tissue between the base and the apex, where V = Q, and therefore V/Q = 1. Beyond this point, V > Q, and therefore V/Q > 1 near the apex of the lungs (V/Q = 3.0 at apex). Therefore, the general trend is that V/Q increases moving vertically upwards from base to apex. The majority of lung tissue sits at a V/Q lower than 1, this is why the overall average V/Q = 0.8. Pathological variation in V/Q Normal average V/Q of lung tissue is around 0.8. This V/Q can be changed to one of two extremes due to variation of one of the variables: R-L shunt – Some alveoli become unventilated, for example due to pulmonary oedema. This forms an R-L shunt: a portion of blood from the right side of the heart which does not get oxygenated by the lungs. At this shunt, V = 0. Therefore, V/Q is 0. Here, PACO2 and PAO2 in the alveoli stabilise to the pressures in the venous blood reaching the alveoli (PA = PV). PACO2 increases (from 5 kPa at normal to 6 kPa). PAO2 decreases (from 13 kPa at normal to 5 kPa). Lack of perfusion – Lack of blood supply to a particular portion of lung tissue may be due to a pulmonary embolism. In this scenario, Q = 0, therefore V/Q = ∞. Here, PACO2 and PAO2 in the alveoli stabilise to pressures in the inspired air (PA = Pi).  PACO2 decreases (from 5 kPa at normal to roughly 0 kPa). PAO2 increases (from 13 kPa at normal to 20 kPa). Between these two extremes, increase in V/Q leads to: Decrease in PACO2 towards 0 kPa. Increase in PAO2 towards 20 kPa. Decrease in V/Q leads to: Increase in PACO2 towards 6 kPa. Decrease in PAO2 towards 5 kPa. Physiological adjustment of the V/Q ratio If the V/Q ratio in a particular region becomes increased or decreased for a reason such as those mentioned above, the system initiates reflexes in order to restore V/Q to its normal value. If V/Q is elevated: for example due to pulmonary embolism. Elevated V/Q leads to increase in local PAO2 (hyperoxia) and decrease in PACO2 (hypocapnia) in that region of lung tissue. The system needs to reduce V/Q back to its normal level. To do this: ○ Q must be increased -> This is done by vasodilation. ○ V must be decreased -> This is done by bronchoconstriction. If V/Q is reduced: for example due to pulmonary oedema. Reduced V/Q leads to decrease in PAO2 (hypoxia) and increase in PACO2 (hypercapnia) in that region. The system needs to increase V/Q back to its normal level. To do this:  ○ Q must be decreased -> This is done by vasoconstriction. ○ V must be increased -> This is done by bronchodilation. Hypoxic pulmonary vasoconstriction As stated above, in states of hypoxia due to a reduced V/Q, a vasoconstriction reflex is initiated. In addition to decreased blood flow to restore V/Q, this also has the benefit of diverting blood away from poorly ventilated areas of the lung. Blood is diverted to better ventilated areas. This vasoconstriction in response to hypoxia is unique to pulmonary arterioles and is known as hypoxic pulmonary vasoconstriction (HPV). In other arterioles of the body, hypoxia would lead to the opposite – vasodilation – in order to receive more blood. The mechanism for this constriction may be as follows: 1. Hypoxia inhibits exit of K+ ions from smooth muscle cells of blood vessels (via K+ channels) 2. This leads to membrane depolarisation. 2+ 2+. 3. Voltage-gated Ca channels open, causing influx of Ca 4. This initiates smooth muscle contraction -> vasoconstriction. Changes in V/Q mismatch due to disease The graph on the right shows a healthy individual, with well-matched ventilation and perfusion. Regions of the lung which are highly ventilated are also receiving adequate perfusion. Poorly ventilated areas are not receiving much blood flow. This graph on the left shows an unhealthy lung in a patient with bronchitis and emphysema (COPD). Here, a highly affected, poorly ventilated area is receiving a lot of blood flow. Since ventilation in that area is very low (almost 0), V/Q is very low and almost 0 in that region. This region is a functional shunt. This leads to hypoxemia (low PaO2), causing the patient to breathe more. In healthier portions of the lung, there will be an increased ventilation (due to breathing more). This region will have a high V/Q, which compensates for the area of low V/Q. to normalise arterial PaCO2. A-a difference The difference in alveolar and arterial PO2 can be used to identify issues in the lungs. An abnormally elevated A-a difference (>1, depends on age) can be due to: Excessive V/Q mismatch, for example due to shunting as in the above example. Impaired diffusion across the alveolar-capillary membrane, for example due to fibrosis. If a low PaO2/hypoxemia (arterial oxygen) was caused ONLY by hypoventilation, the A-a gradient would be normal. Diseases/interventions which can cause increased A-a difference Whole lung diseases/interventions ○ Pneumothorax ○ Congenital diaphragmatic hernia ○ Surgery on a single lung Only Part of lung affected ○ Pneumonia ○ Asthma ○ Bronchitis ○ Emphysema ○ Aspiration (breathing in) of stomach contents ○ Pulmonary embolism ○ Septicaemia – blood poisoning ARDS (adult respiratory distress syndrome) or RDS (infant)