C25+Supplementary Respiratory Guide 2025 PDF

Foundations for Practice MED1028 Respiratory System Supplementary Guide to lectures THIS GUIDE is intended for use in conjunction with the other components of the module, lectures, practicals, tutorials and self-directed study, but...

Foundations for Practice MED1028 Respiratory System Supplementary Guide to lectures THIS GUIDE is intended for use in conjunction with the other components of the module, lectures, practicals, tutorials and self-directed study, but particularly the respiratory lectures. You should read the guide before the lectures. Listening to the lecture should be used to help you to signpost emphasis, understand logic, read graphs and use data and simple equations. Important topics are usually explained more than once in various formats, so that those who cannot follow the first time will have other opportunities in the overall experience. Less important topics will only be presented once, so you will need to follow conscientiously to avoid missing those topics. These pre-circulated notes should allow you to concentrate on following the logical development of the subject during the lecture without the distraction of writing voluminous notes at the same time. Each chapter covers the content of a lecture. The lecture slides are embedded as figures in this guide. The figures are numbered within chapters and are projected and discussed in lectures. CONTENTS Chapter Page 1. Ventilation; lung volumes and capacities 2 2. Alveoli: restrictive ventilatory defect 7 3. Airways: obstructive ventilatory defect 16 4a. Gas transport by blood 23 4b. Carbon dioxide transport by blood 29 5. Transfer of gases across the alveolo-capillary membrane 33 6. Regulation of respiration 39 7. Pathophysiologies 45 List of pulmonary function tests 52 Index 53 Chapter Page 1 Ventilation; lung volumes and capacities © Dr J P Jamison 1. Ventilation: lung volumes and capacities BREATHING and BEATHLESSNESS (DYSPNOEA) Inspiration: muscles contract and do work Expiration: passive in healthy breathing – no muscle work Breathlessness: increased work of breathing You study structure and the movements of breathing in anatomy, so this topic will not be repeated in detail. However the anatomy of the structures and their nomenclature is essential to enable you to understand the physiology of respiration. STRUCTURE OF RESPIRATORY SYSTEM AND A MODEL OF BREATHING Two anatomical terms which are particularly important to understand are ‘alveoli’ and ‘airways’. The alveoli are millions of tiny air filled, thin walled sacs which are well perfused with capillaries. The alveoli are responsible for gas exchange and their elasticity enables lung inflation and deflation (Figure 1.1). The airways are the tubes through which air flows on the way to and fro between the alveoli and the atmosphere. Note that the term ‘airways’ does not include ‘alveoli’. Figure 1.1 Structure of the respiratory system and a simplified model. Airways are the conducting tubes - nose or mouth, larynx, trachea, bronchi and bronchioles. The alveoli have elastic walls which allow air into the lungs, provide force to drive air out and allow gas exchange. Alveoli are not included in the term ‘airways’. The respiratory bronchioles have some alveoli opening off them so they have the hybrid function of both conducting air flow and gas exchange. The lungs are invested with a pleural membrane which has two layers – visceral, on the lung; and parietal, lining the chest wall. The layers are continuous forming a sealed space filled with a small amount of fluid – the pleural cavity. The model of the respiratory system on the right is a rubber balloon enclosed in a syringe. The neck of the balloon is analogous to the airways. The bladder of the balloon is analogous to the alveoli and the piston of the syringe is analogous to the diaphragm. The space between the syringe barrel and the balloon is analogous to the pleural cavity. Pulling the piston down will draw air into the balloon, while release of the piston will allow the elastic recoil of the balloon to expel air from the balloon. Nose Mouth Tonsils Larynx Pharynx Trachea Bronchi Pleural Bronchioles Respiratory bronchiole cavity Rib Intercostal muscle Alveoli Diaphragm At rest the muscles needed to inhale are the external intercostal muscles and the diaphragm. During inspiration the diaphragm descends to increase the vertical dimension of the chest cavity. The ribs move by a ‘bucket handle’ and ‘pump handle’ movement to increase the transverse and antero- posterior dimensions (Figure 1.2). The muscles are striated voluntary muscles innervated by somatic nerves. (Note that the autonomic nervous system has no role whatsoever in the contraction of these muscles.) Expiration, in quiet breathing, does not require muscle contraction as it is driven by elastic recoil of the lungs (alveoli). Muscles are available in both inspiration and expiration to use when more force is required such as during exercise or if there is impairment of lung function. A model of the respiratory system based on a rubber balloon illustrates breathing (Figure 1.1). Active work is needed to pull down the syringe, but left alone the balloon will expel its air by its own elastic recoil. When Chapter 1 Page 2 Ventilation; lung volumes and capacities © Dr J P Jamison patients complain that they are “breathless” (dyspnoeic) it is often because the muscles are experiencing increased load to breathe. The model shows the 2 locations where increased resistance to inhalation can occur: narrow neck (airway) and stiff bladder wall (alveolar wall). Increased work will also be needed if more air is inhaled. The learning points from this simple model are that the symptom of breathlessness (ie when more work is needed to breathe) may occur because of (1) stiff alveolar walls or (2) narrowed airways or (3) increased minute ventilatory volume. Figure 1.2 Antero-posterior and lateral chest X-rays in expiration and inspiration. Note the changes in the height of the diaphragm and the orientation of the ribs. The dimension of the chest cavity increases in all three directions. EXPIRATION INSPIRATION Ches LUNG VOLUMES Measuring gas volumes is quite difficult to do accurately because volume changes with pressure and temperature in accordance with Boyle’s law and Charles’ law. Respiratory gas volumes are reported at body temperature and pressure saturated with water vapour (BTPS). When breathed out, air changes its temperature very quickly and is often collected and measured at room temperature. The volume is then corrected to BTPS. A spirometer is a device for measuring lung volumes. There are various types. The water-filled spirometer is illustrated in Figure 1.3. This type provides very accurate measurements of volumes, but is unable to record rapid changes in volume accurately and is a risk for infection. There are dry spirometers of various types which can record rapidly expired volumes, but the most common modern technique is to record air flow rate by flow meter and obtain volumes by integrating flow with respect to time. There are many types of flow meter eg cooling a hot wire, a rotating vane, pressure drop across a wire grid, or Doppler ultrasound. Lung volumes and capacities are shown in Figure 1.3. This figure illustrates a subject breathing through a tube connected to air trapped over water. Movements of the drum record the volume of air against time. The volumes and capacities are named. The convention is that if a lung volume may be subdivided into named volumes it is called a ‘capacity’. It is essential to know the names as otherwise you will not understand subsequent explanations which refer to these entities. Chapter 1 Page 3 Ventilation; lung volumes and capacities © Dr J P Jamison Figure 1.3 Water-filled spirometer being used to measure lung volumes. The trace shows volume against time during resting breathing followed by a full inspiration and finally a full expiration. Volume of air inhaled – upward Water filled exhaled - downward spirometer Full breath in INSPIRATORY RESERVE VOLUME VITAL TOTAL TIDAL VOLUME CAPACITY LUNG Quiet breathing EXPIRATORY RESERVE FUNCTIONAL CAPACITY VOLUME RESIDUAL RESIDUAL CAPACITY VOLUME 0 Full breath out MINUTE VOLUME = TIDAL VOLUME  RESPIRATORY FREQUENCY Tidal volume is the volume of air breathed in and out in normal breathing. The volume of air breathed in one minute (minute volume) is the volume of air breathed in one breath (tidal volume) multiplied by the number of breaths taken in one minute. There is enormous reserve of function in the lungs. After a normal inspiration, it is possible to take in more air. The additional volume available is called the inspiratory reserve volume. Similarly, after a normal expiration, an additional volume of air can be exhaled, called the expiratory reserve volume. Even with a maximal expiration, the lungs cannot be emptied. The chest wall comes to a limit of movement and some small airways close towards the end of exhalation, trapping air behind them. The volume of air left in the lungs after a maximal expiration is called the residual volume. Do not confuse this volume with dead space which is the volume of air in the lung which cannot take part in gas exchange. In health the dead space is confined to the air in the airways. Because the residual volume cannot be exhaled it cannot be measured with a simple spirometer. For this, the dilution of a marker gas is required (Figure 1.4). Figure 1.4 The dilution of helium is used to measure lung volumes which cannot be exhaled. This is part of the gas transfer practical. Vital capacity of helium After inhalation and mixing with mixture is inhaled the residual volume, the helium concentration is diluted RV+VC RV Helium is not taken up by blood or lost from alveoli The dilution of the helium enables the residual volume to be obtained Total lung capacity is the volume of air in the lungs at maximal inspiration. Vital capacity is the maximal volume of air which can be expired from a maximal inspiration. Functional residual capacity is the volume of air in the lungs at the end of a quiet expiration. Inspiratory capacity is the maximal volume of air which can be inhaled from the end of a quiet expiration. Each of the capacities may be subdivided into the previously defined lung volumes: eg the functional residual capacity may be subdivided into the sum of the expiratory reserve volume and the residual volume. Chapter 1 Page 4 Ventilation; lung volumes and capacities © Dr J P Jamison Minute ventilatory volume The minute ventilatory volume is the volume of air breathed each minute. It is calculated as the volume of air breathed in one breath multiplied by the number of breaths taken in one minute. This calculation is equivalent to the calculation of cardiac output as stroke volume multiplied by heart rate. The minute ventilatory volume is of equivalent importance to the respiratory system as cardiac output is to the cardiovascular system At rest a typical tidal volume is ½ L and respiratory frequency is 12 breaths per minute. This gives a minute volume of 6 L/min. When severe demand is placed on ventilation, about 80% of the reserve volumes may be used to increase the tidal volume and the respiratory rate can be increased to 40 breaths per minute. The forced expiratory volume in one second FEV1 (see index) can be breathed 40 times per minute which leaves only one second to breathe in and ½ second to breathe out. Ventilation >100 L/min may be achieved in severe exercise. TECHNICAL TERMS: LUNG COMPLIANCE AND AIRWAY RESISTANCE LUNG COMPLIANCE (Chapter 2) Lung compliance is the increase in lung volume per unit of pressure measured statically at the functional residual capacity. The reciprocal of compliance is elastance (also called elastic recoil). AIRWAY RESISTANCE (Chapter 3) Airway resistance is the pressure required to drive one unit of flow through the airways. (The reciprocal of resistance is conductance.) THE RESPIRATORY CYCLE: Pressures, flow, and volume during inflation and deflation Air flows into the alveoli of the lungs during inflation when the pressure in the alveoli is less than atmospheric pressure. This negative pressure is generated by increased distension of the alveoli. The increased distension of the alveoli is caused by more negative pleural cavity pressure created by descent of the diaphragm and outward movement of the ribs. (Figures 1.5 and 1.6) Figure 1.5 This diagram is to further explain the learning points on page 3. At rest, pleural cavity pressure (Ppl) is negative with respect to atmospheric pressure. During inspiration, Ppl becomes even more negative, applying a distending pressure on the alveoli. The elastic recoil in the alveolar walls applies a compressive force on the air in the alveoli, therefore alveolar pressure (PAlv) is less negative than Ppl. During inspiration, PAlv is negative with respect to atmospheric pressure. Thus the total pressure gradient between the pleura and the atmosphere is made up of two components: between the pleural cavity and the alveolar air ie across the alveolar walls and between the alveoli and the atmosphere ie across the airways. These two components represent the two mechanical factors in the lungs which need to be overcome to inflate the lungs: elastic recoil of the alveolar walls and resistance to flow of air through the airways. Patmos Airways Across Across alveolar airways Chest wall walls { { PAlv Ppl-Patmos = (Ppl – PAlv)+ (PAlv- Patmos) Alveoli Ppl Chapter 1 Page 5 Ventilation; lung volumes and capacities © Dr J P Jamison Figure 1.6. The respiratory cycle. This diagram is the respiratory equivalent of the cardiac cycle. Pressures are shown with respect to atmospheric pressure. Alveolar pressure (PAlv) is negative during inspiration and positive during expiration. There is proportionality between PAlv and flow. The proportionality constant is airway resistance (1.1 cmH2O∙s∙L-1). When alveolar pressure is zero, there is no flow. Pleural pressure (Ppl) is negative throughout the respiratory cycle. Therefore if the seal to the atmosphere is broken, air is sucked into the pleural cavity (pneumothorax) and the lung collapses. It becomes more negative during inflation. This is because more pressure is needed to stretch the alveolar walls when the alveoli are more distended. Ppl is, however, not proportional to lung volume – its greatest negativity occurs before the inspiration is completed ie Ppl is out of phase with volume. The reason is that Ppl also has to generate the negative PAlv during inflation to overcome airway resistance while air is flowing. Air is not flowing at two points – end expiration and end inspiration. These two static points may be used to calculate lung compliance. In the cycle shown, the increase in volume between these two points was 500 mL for a pressure increase of 3 cmH 2O. This makes the lung compliance 167 mL∙cmH2O-1. 2 Flow INSPIRATION EXPIRATION L/s 1 Flow Palv 0 5s Volume Pressure -1 cm H2O Ppl -2 2.5 -3 Volume -4 3 -5 -6 WORK OF BREATHING To create the additional negative pleural cavity pressure required to inflate the lungs requires muscular work, done by the skeletal muscles the diaphragm and the external intercostal muscles. The work done is the pressure × volume of air inhaled. Increased pressure is required if either lung compliance decreases (‘stiff’ alveoli) or airway resistance increases (narrowed airways). Increase in volume of air breathed (minute volume) also increases the work of breathing. Increased work of breathing causes dyspnoea (breathlessness). Accessory muscles are used if the work load is very high. Chapter 1 Page 6 Alveoli: restrictive ventilator defects © Dr J P Jamison 2. Alveoli: restrictive ventilatory defect Functions of alveoli The alveoli have gas exchange and mechanical functions. This chapter is concerned with their mechanical function: it is the alveoli which expand during inhalation and which provide the force for expiration in quiet breathing. Without the elasticity of alveoli it would not be possible to breathe! Lung compliance Lung compliance (distensibility of the lungs) may be measured in human subjects by measuring volumes with a spirometer and pleural cavity pressure using an oesophageal balloon. This latter is a balloon attached to the end of a catheter which is passed into the oesophagus through the nose. As the oesophageal wall is flaccid (when not swallowing) the catheter effectively measures pleural cavity pressure through the balloon wall, the oesophageal wall and the pleural membrane. The reason for the balloon is to prevent the mucosa from blocking the catheter tip. Figure 2.1 shows the static plot of lung volume against pleural cavity pressure (negative to the right) measured using an oesophageal balloon. A similar plot may be obtained in isolated lungs, where positive pressures are used to inflate. Figure 2.1 Lung compliance: pressures and volumes are measured statically. The pressure is the distending pressure ie the difference between alveolar pressure and pleural cavity pressure. When measured statically alveolar pressure equals atmospheric pressure. The pressure shown is pleural cavity pressure which is negative with respect to atmospheric pressure and becoming more negative to inflate the lungs.FRC: functional residual capacity; C: lung compliance. VOLUME DV DV C= FRC DP DP -2 -5 PRESSURE cm H2O Compliance is obtained from the slope of the plot of volume against distending pressure with the lung stationary (ie no air flow so that none of the measured pressure is being used up overcoming the resistance to air flow offered by the conducting airways). The slope is taken at the steepest point which occurs at the functional residual capacity (volume of air in lungs at the end of quiet expiration). Graphs for compliance of the chest wall and the lungs plus the chest wall are also available in your texts, but compliance of the lung is more important as it is more prone to disease. Alveoli: structure and pathophysiology The structural basis of the ability of the alveolar walls to stretch is (a) elastin fibres and (b) surface tension. The wall is very thin (Figures 2.2-2.4). Division of the lung into millions of these tiny air sacs increases the surface area enormously. Chapter 2 Page 7 Alveoli: restrictive ventilator defects © Dr J P Jamison Figure 2.2 The alveolar wall. The wall between the blood in the pulmonary capillary and the air is composed of a single layer of epithelial cells (Type 1 pneumocytes), a single layer of endothelial cells and an interstitium, EPITHELIUM INTERSTITIUM ENDOTHELIUM AIR RED BLOOD CELL Figure 2.3 Alveolar epithelium: Types 1 and 2 pneumocytes. The principal epithelial cells are thin squamous cells (Type 1). Their thinness is important for gas diffusion (see later). Amongst these cells there are thicker cells with plentiful cytoplasm and lamellated inclusion bodies. These contain a collection of material known as surfactant which they disgorge onto the air surface. This material reduces surface tension. TYPE 2 PNEUMOCYTE Surfactant Lamellated inclusion body Figure 2.4 Schematic structure of the alveolus. The diffusion distance is short. The area available is large 70-100 m2. Air Surfactant in Epithelial cell Alveolus Basement membrane 0.2mm Elastin fibres Basement membrane Blood Endothelial cell in Capillary Chapter 2 Page 8 Alveoli: restrictive ventilator defects © Dr J P Jamison FACTORS AFFECTING LUNG COMPLIANCE Surface tension and the roles of surfactant The compliance (and elastic recoil) of the lung is based on the ability of these thin alveolar walls to stretch. The two factors in the wall which account for this property are surface tension and elastin fibres (Figure 2.4). Each makes approximately equal contributions. The surface tension arises from the interface between the air and the wet surface. The surface of the epithelial cells is wet because they would die if they dried out. Surface tension arises from the affinity of water molecules for each other leading to them effectively trying to reduce the number of water molecules on the surface which generates a tangential force tending to collapse the alveoli and resist their distension. This force is quite large. However it is reduced by the secretion of a collection of molecules on the surface called surfactant. Surfactant reduces surface tension. The molecules have a head and tail structure. The head is hydrophilic and dissolves in the water. The tail is fatty and hydrophobic and lines up towards the air, creating a new surface with a lower surface tension. This increases lung compliance and reduces the work of breathing. Surfactant reduces the tendency of small alveoli to collapse. It contributes to the stability of small alveoli by reducing their surface tension even more because there is a relatively more surfactant available for their smaller surface. The law of Laplace is that the pressure required for stability of a spherical surface, P, is related to the tension in the wall, T, and the radius of curvature, R as follows: P=2T/R. This would suggest that small alveoli would generate more pressure and therefore empty into large alveoli if they all had the same tension. The greater concentration of surfactant on the surface of small alveoli reduces their T which helps prevent small alveoli from collapsing. There is also benefit to the pulmonary capillaries. There is an outward distending pressure on these capillaries by surface tension and surfactant reduces this. Fluid and material tend to egress from over-distended vasculature into the air spaces and this is also prevented by surfactant. The contributions of surface tension and surfactant vary with lung volume and its inflation history. This is most clearly shown in the first breath of air after birth (Figure 2.5). Compliance of the lung is low when inflating from no air in the lungs, increases after inflation and is higher during deflation than during inflation (hysteresis). The difference between inflation and deflation can be attributed to surface tension. (The evidence is that compliance is increased and hysteresis is absent when isolated lungs are inflated with saline instead of air.) Hysteresis may be explained in part by limitation of surface availability of surfactant caused by it going into solution when the lung is deflated. Hysteresis is minimal over the range of lung volumes used in normal breathing. Surfactant deficiency is discussed below. Chapter 2 Page 9 Alveoli: restrictive ventilator defects © Dr J P Jamison Figure 2.5 Static pressure volume plots for newborn lung. When the newborn infant takes the first breath and the lungs are inflated from zero volume, compliance is very low at first, but increases during inflation. Compliance is even greater during deflation. The difference in the pressure volume plot between inflation and deflation is called hysteresis. Initially the low compliance can be explained by the Law of Laplace. Furthermore, it is thought that surfactant goes into solution when the lung is deflated so that, on subsequent inflation, there is too little surfactant on the surface to lower surface tension. During deflation, surfactant has come out of solution and more is available on the surface enhancing compliance. At high lung volumes, a volume limit is approached - some folded collagen becomes straightened and chest wall deformation is limited. Volume limit More surfactant on surface during deflation VOLUME Hysteresis Less surfactant on surface during inflation Law of Laplace, small R PLEURAL CAVITY PRESSURE (-) P= 2T alveolar collapse R Alveolar wall interstitial fibres and decreased compliance The elastin fibres are laid down by fibroblasts. The usual fibre they produce elsewhere is collagen which is un-stretchable – like string. The elastin is like rubber ie it stretches. In pulmonary fibrosis the elastin fibres are replaced by collagen fibres. This makes the alveolar walls stiff ie decreases lung compliance (figure 2.6). Restrictive ventilatory defects; lung volumes and compliance This term ‘restrictive ventilatory defect’ refers to restriction of lung volumes. The term ‘restriction’ is used technically for this purpose only and must not be used to refer to narrowing of airways which is referred to as obstruction. The minute volume tends to be preserved until late in the disease because minute volume is essential for maintenance of the blood gases. All other volumes are decreased. If there is any doubt about the diagnosis of restriction, the total lung capacity is taken as the preferred lung volume for the diagnosis. The restrictive ventilatory defect is usually due to the alveolar walls being stiff and hard to inflate ie decreased lung compliance. It can also be due to chest wall disease or space occupying lesions in the chest cavity. Lung volumes are usually measured rather than lung compliance. When lung compliance is decreased, if the chest wall is healthy and the subject makes a maximal effort to inhale fully then a normal, maximally negative pressure will be applied in the pleural cavity to inflate the lungs. If the lungs fail to inflate to a normal total lung capacity then the increment of volume per unit pressure must have become decreased ie the lung compliance is decreased. The measurement of volumes is mostly used to determine this condition rather than the measurement of lung compliance directly because lung compliance needs pleural cavity pressure measurement which is uncomfortable and difficult, requiring the passage of an oesophageal balloon. In theory surfactant deficiency would cause a restrictive defect. However the patients who experience surfactant deficiency are too ill to have their lung volumes measured. Hence the principal cause of the restrictive ventilatory defect is pulmonary fibrosis. Chapter 2 Page 10 Alveoli: restrictive ventilator defects © Dr J P Jamison The clinical significance of a restrictive ventilatory defect is that the work of breathing will be increased because increased load will be felt by the respiratory muscles to breathe a normal minute volume. Therefore the patient will complain of dyspnoea. The functional residual capacity (FRC) is the volume of air in the lungs at the end of a quiet expiration. The muscles can relax at this volume because there is a balance between elastic recoil of the lungs (collapsing pressure) and the elastic recoil of the chest wall (distending pressure). A patient with a restrictive defect breathes at a lower functional residual capacity (Figures 2.6 and 2.7). This helps to reduce the work of breathing because the load on the respiratory muscles is decreased when the stiff lungs are under less stretch. The balance between the elastic recoil of the lungs and the elastic recoil of the chest wall is shifted to smaller lung volumes by the decreased compliance. Figure 2.6 Static pressure volume plots in a normal subject compared with a subject with a restrictive ventilatory defect (red). The underlying pathophysiology of the restrictive ventilatory defect is decreased lung compliance. Note that the functional residual capacity (FRC) is decreased in this condition as well as the total lung capacity (TLC). TLC NORMAL VOLUME TLC / FRC DECREASED COMPLIANCE FRC/ PRESSURE Figure 2.7 The model of the respiratory system applied to lung volumes in normal, obstructive and restrictive defects. In obstruction (increased airway resistance, Raw) there is an increase in the functional residual capacity (FRC). This is caused by increased alveolar tethering being used to help hold the airways open and is called hyperinflation. In restriction (decreased compliance, C), all lung volumes, including the FRC, are reduced (restricted). Normal Obstructive Restrictive ↑Raw ↓C ↑ FRC ↓ FRC Surfactant deficiency Surfactant deficiency causes respiratory distress in premature new born infants (Figure 2.8). Type 2 pneumocyctes develop their ability to secrete surfactant late in foetal development. The deficiency of surfactant decreases lung compliance. The increased surface tension dilates pulmonary capillaries and draws fluid. A hyaline membrane forms on the alveoli impairing gas exchange. Surfactant deficiency also occurs in adult respiratory distress syndrome. This is a very severe disease and requires intensive care treatment. It is therefore not a cause of simple restrictive defects in ambulant patients. Chapter 2 Page 11 Alveoli: restrictive ventilator defects © Dr J P Jamison Figure 2.8 Surfactant deficiency. Respiratory disease of the premature newborn. The first breath of life requires more pressure than subsequent breaths in healthy newborn infants (Figure 2.5), but is even harder for premature newborn infants because of surfactant deficiency. It can be treated by surfactant instillation to the lungs. normal VOLUME newborn respiratory disease of premature newborn surfactant deficiency PRESSURE Alveolar wall interstitial fibres and increased compliance Another defect which may occur in compliance is an increase in compliance (Figure 2.9). This occurs when elastin fibres are destroyed rather than replaced. In the disease emphysema, elastin fibres are destroyed by enzymes. This is often the result of cigarette smoking which activates elastase release from inflammatory cells. A rarer cause is the congenital disease 1-anti trypsin deficiency. This enzyme breaks down elastase and therefore these patients have excessive elastase and get emphysema at a young age. They have increased lung volumes (Figure 2.9) and airway obstruction from the loss of alveolar wall tethering (Figure 2.10). Figure 2.9 Increased lung compliance. Static pressure volume plot is steeper and lung volumes are increased. It might appear easier to breathe as there is less work against lung elastic recoil but the loss of alveolar tethering causes increased airway resistance and the overall effect is increased work of breathing. INCREASED COMPLIANCE VOLUME NORMAL FRC/ FRC PRESSURE Chapter 2 Page 12 Alveoli: restrictive ventilator defects © Dr J P Jamison Figure 2.10 The alveolar walls are attached to the small airway walls, exerting an outward tension (alveolar tethering) which help hold the small airways open. Note also the larger cross-sectional area of the two branch airways, which offer a lower resistance to flow (see chapter 3). FORCED EXPIRATORY MANOEUVRE In clinical practice the measurement of the forced expiratory manoeuvre is the most frequently used pulmonary function test. The term used in clinical practice for recording this manoeuvre is ‘spirometry’. The restrictive ventilatory defect is more commonly diagnosed from this manoeuvre rather than the more definitive full lung volume measu rements. You will be carrying out this manoeuvre for yourselves in the practical laboratory, so the detail will be deferred to those classes. Briefly, the manoeuvre is: inhale fully, then without hesitation, exhale as fast and as far as possible. The usual plot obtained is volume expired against time (Figure 2.11), but further information is available from records of flow against volume in both expiration and inhalation. Peak expiratory flow occurs early in the forced expiration and may be monitored with inexpensive equipment. Flows at low lung volumes are less effort dependent and reflect small airways better. Inspiratory flow impairment suggests extra-thoracic obstruction while expiratory impairment suggests intra-thoracic obstruction. Chapter 2 Page 13 Alveoli: restrictive ventilator defects © Dr J P Jamison Figure 2.11 Volume time plots during the forced expiratory manoeuvre in a normal subject, a subject with a restrictive ventilatory defect and a subject with an obstructive ventilatory defect. The air comes out fastest early in expiration (peak flow), followed by a progressive decrease in expiratory flow rate until no more air can be blown out. Two measurements are taken: the volume expired after the first second (forced expiratory volume in one second, FEV 1) and the final maximal volume expired (forced vital capacity, FVC). Over 70% of the FVC should be expired in the first second. It is important to calculate the proportion of the FVC expired in the first second (FEV1/FVC ratio). In the restrictive ventilatory defect, the FEV1 and FVC are reduced in parallel along with the other lung volumes. The defect is in the inspiratory phase of the manoeuvre when a maximal inflationary pressure fails to get enough air in because the alveolar walls are stiff and hard to inflate. However there is nothing wrong with the airways so there is fast flow of the air out of the lungs. Therefore the FEV 1/FVC ratio is not decreased. Indeed the ratio is often increased as the flow is assisted by the increased elastic recoil of the lungs. PRESSURES To move air in and out of the lungs, pressure is required. Pressures during a normal respiratory cycle are shown in Figure 1.6. Figure 2.12 shows the relationships between pleural cavity pressure and volume in a patient with restriction. The scales for volume and pleural cavity pressure on the diagram (Figure 2.12) have been chosen so that the red-brown line which represents volume could also represent pleural cavity pressure if measured with the lung stationary. The actual pleural cavity pressure during dynamic respiration (turquoise line) is identical to the red-brown line at the beginning and end of inspiration, which are static points. Lung compliance can be calculated between these two points. In clinical practice, compliance is rarely measured because it is uncomfortable to have a naso- oesophageal balloon inserted. The measurements are therefore limited to lung volumes, the patient’s effort to generate pleural cavity pressures being assumed. However the interpretation of the restrictive ventilatory defect as loss of compliance and therefore caused by an alveolar wall disease is important. Chapter 2 Page 14 Alveoli: restrictive ventilator defects © Dr J P Jamison Figure 2.12 Respiratory cycle: pleural cavity pressure and lung volume against time in restriction. Compare Figure 1.6. The brown line shows the lung volume, increasing downwards (scale on right). The increase in lung volume is fastest in mid-inspiration when the flow is greatest. The turquoise line shows pleural cavity pressure. This is negative throughout the respiratory cycle in quiet respiration, most negative towards the end of inspiration. Between end expiration and end inspiration (lung is stationary at these times) the increase in volume was 500 mL caused by approximately 8 cmH2O change in pleural cavity pressure. Thus the lung compliance is 62.5 mL∙cmH2O-1. This compliance is reduced compared to the normal shown in Figure 1.6. The functional residual capacity is also reduced. INSPIRATION EXPIRATION 0 Volume Pressure cm H2O Ppl -2 2 Volume L 2.5 -10 0 Time s 5 The work of breathing The work of breathing is the product volume × pleural pressure during inspiration. Expiration is normally passive, being driven by elastic recoil of the lungs. High pressures may be caused either by increased airway resistance or increased elastic recoil (decreased lung compliance). High pressures mean more load on the muscles. There is also more work done if the minute volume is increased. Increased work of breathing will cause the symptom dyspnoea (breathlessness). If a patient complains of breathlessness they probably have increased work of breathing. You must consider whether there is increased pressure needed to inhale and whether this increased pressure is due to stiff alveoli or narrow airways. Alternatively the cause of dyspnoea could be increased minute volume. Chapter 2 Page 15 Airways: obstructive ventilatory defects © Dr JP Jamison 3. Airways: Obstructive ventilatory defect Two obstructive airway diseases, asthma and chronic obstructive pulmonary disease, make this an important topic because these diseases cause so much ill-health in the community. The airways have the primary function of conducting air between the atmosphere and the alveoli. The principle parameter which measures this function is resistance of the airways to flow (AWR). AWR remains unaffected by airflow rate within limits. Thus air flow is proportional to the pressure gradient between the atmosphere and the alveoli (Flow = PAlv / AWR, Ohm’s law). The definition of AWR is therefore the pressure in the alveoli (PAlv) which gives one unit of air flow rate. In patients whose airway resistance has increased, higher alveolar pressures are used to drive normal flow rates (Figure 3.1). The higher pressures mean the subject has to do more work to breathe and will feel breathlessness. The subject does this extra work because maintaining the flow is essential to maintaining minute volume and minute volume is essential to maintaining the blood gases. Figure 3.1 Superimposed respiratory cycle records from a subject with normal airway resistance (solid line) and doubled airway resistance (dashed line). Alveolar pressure is shown in magenta and air flow rate in blue against time. With increased airway resistance flow is maintained at the cost of increased pressure and therefore dyspnoea. 2 INSPIRATION EXPIRATION L/s Flow 1 Palv normal 0 Palv increased 5s airway resistance Pressure -1 cm H2O -2 The reason that laminar flow is proportional to pressure is that the resistance to flow is determined by the dimensions of the airways and the viscosity of air. The full mathematical description by Poisieulle is: F= (P1-P2)×rL, where F is flow rate, P1-P2 is the pressure gradient, r is the radius of the tube, L is its length and  is the coefficient of viscosity. From a medical point of view, the radius is the most important because it is raised to the fourth power and changes with disease. This formula may be simplified by replacing 8L/r4 by airway resistance (AWR), which then becomes ‘Ohm’s law’, as above. Turbulent flow is where not all flow is parallel to the walls of the tube (Figure 3.2). The principle cause for turbulence is that the mean velocity is increased (note: ensure that you understand the difference between velocity in cm/s and volume flow in L/s). The clinical significance of turbulent flow is that it enables the diagnosis of narrowed airways. Abnormal turbulence occurs in diseases which narrow the airways because to carry the same volume flow requires increased flow velocity. Laminar flow is silent whereas turbulent flow vibrates the walls of the airways and produces sound. This may be loud enough for the patient to hear as a wheeze, or it may need auscultation with a stethoscope to hear, when it is called a rhonchus. Thus wheeze or rhonchi indicate increased airway resistance. Chapter 3 Page 16 Airways: obstructive ventilatory defects © Dr JP Jamison Figure 3.2 Laminar and turbulent flow. In laminar flow all flow is parallel to the walls. The central laminae flow at the fastest velocity while the lamina at the wall is stationary (velocity shown by arrow lengths). Viscosity is the shear force arising from the slippage between adjacent laminae. In turbulent flow there are multiple directions – swirls and eddies. This is less efficient and increases the resistance to flow. It also generates sound. Laminar flow Turbulent flow Vibration → wheeze Figure 3.3 Cross-sectional area of airways increases exponentially from a few square centimetres at the trachea to square metres at the respiratory bronchioles. Flow velocity slows until stationary in the alveoli. Figure 3.4 Airway resistance by generation of intrathoracic branching Trachea Resistance of each generation Bronchiole Airway generation 15 Most airway resistance is in the upper airways - nose or mouth, pharynx and larynx. Of the lower airways, the large airways contribute more resistance than the small ones because of their greater number ie the bronchioles offer less resistance than the bronchi (Figures 3.3, 3.4). Note that this is the reverse of the vasculature where arterioles offer more resistance than the arteries. The cause is that, despite their small diameter there are so many small airways that the total resistance of the generation is Chapter 3 Page 17 Airways: obstructive ventilatory defects © Dr JP Jamison low. At every branch the cross-sectional area increases substantially and resistance decreases (Figures 2.10, 3.3, 3.4). Obstructive ventilatory defects Increased airway resistance is a major cause of morbidity and mortality. The increased load on the respiratory muscles increases the work of breathing and makes the patient feel breathless. Factors affecting airway resistance Pressure can compress airways. There is a difference between intra-thoracic and extra-thoracic airways and the phase of breathing, especially forced breathing (Figure 3.5). Figure 3.5 Dynamic compression of airways during expiratory and inspiratory efforts Intrathoracic airways Extrathoracic airways compressed in compressed in forced expiration inspiration The airways inside the chest are compressed during a forced expiration because the positive pleural cavity pressure is applied to the airways as well as the alveoli. Extra-thoracic airways are compressed during inspiration as the pressure fall along the airways from the mouth means there is a lower pressure in the lumen of extra-thoracic airways than in the atmosphere outside. This is of particular importance in obstructive sleep apnoea, a condition in which the extra-thoracic airways become completely occluded during sleep when the skeletal muscle of the pharynx is relaxed. Factors affecting airway resistance arise from the structural components of the airways (Figure 3.6). Airway resistance is essentially determined by the radius of the airways because this factor is raised to the fourth power (Poisieille’s law) and because the other factors (length and viscosity) don’t change much. Chapter 3 Page 18 Airways: obstructive ventilatory defects © Dr JP Jamison Figure 3.6 Schematic drawing of a bronchiole. Bronchial vein nerve artery Bronchial smooth muscle Epithelium Lamina propria Adventitia Lumen Elastin fibre Alveolar wall Outward tension by alveolar walls holds airway open Factors influencing airway resistance to be considered are in the lumen, in the wall and outside the wall. The lumen is the important dimension determining airways resistance, so it needs to be kept clear. The epithelium has cilia which waft foreign material upwards for expectoration (see below). The wall has bronchial smooth muscle innervated by parasympathetic cholinergic bronchoconstrictor fibres (Figure 3.7). The neurotransmitter is acetylcholine. It combines with a muscarinic receptor on the surface of the bronchial smooth muscle cell membrane. G protein in the bronchial smooth muscle membrane is activated which is linked to inhibition of potassium currents through the cell membrane. As potassium efflux polarises the cell, there is loss of polarisation (depolarisation). The depolarisation causes voltage gated calcium channels to open and calcium enters the cell down its concentration gradient. Calcium is the excitation-contraction coupling agent and the cell contracts. The parasympathetic nerves maintain a resting bronchomotor tone which is subject to diurnal variation (most active 4-6 am). There is a sparse sympathetic nerve presence in bronchi which is distributed largely to the vasculature rather than the bronchial smooth muscle. There are non-adrenergic, non- cholinergic nerves releasing various other neurotransmitters which are subject to current research. There are 2 adrenergic receptors which receive adrenaline form the adrenal medulla and relax airway smooth muscle. The adrenaline combines with the 2 adrenergic receptors on the surface membrane of the bronchial smooth muscle. An intra-cellular mediator is produced by the activation of the adenyl cyclase enzyme (again through a G protein activation) associated with the 2 receptor. This generates cyclic adenosine monophate (cyclic AMP) from adenosine triphosphate. The cyclic AMP diffuses through the cell and relaxes the smooth muscle by inhibition of myosin light chain kinase. There is also some activation of potassium efflux, hyperpolarisation and inhibition of inward calcium flux. You should revise second messengers from Semester 1. There are mast cells and other cells which may release chemicals during inflammation. These inflammatory mediators include histamine, various products of arachidonic acid metabolism - prostaglandins and leukotrienes, and platelet activating factor. These mediators are bronchoconstrictor and also increase airway resistance by increasing capillary leakiness and interstitial oedema. Release of mediators in the inflammatory process in asthma causes an obstructive ventilatory defect, characterised by variability including hyper-responsiveness to inhaled methacholine and reversibility to inhaled salbutamol. Cartilage provides some rigidity in bronchi and the trachea. Chapter 3 Page 19 Airways: obstructive ventilatory defects © Dr JP Jamison Figure 3.7 Structures and substances involved influencing airway resistance. The three sections show the bronchial wall (top section), bronchial smooth muscle (middle section) and the bronchial smooth muscle cell membrane and cytoplasm (lower section). Each section is drawn at increasing magnification. Outside the wall, traction from the elastic fibres in the alveolar walls is very important in maintaining intra-thoracic airway calibre. Their loss is the cause of the obstructive defect in emphysema. Destruction of elastin leads to destruction of alveolar walls, leaving large air spaces in the lung (emphysema) and an increase in airway resistance. Such destruction of elastin usually occurs because of cigarette smoking which interferes with the balance between the synthesis and removal of elastin by enzymes in the lung. The enzyme 1-antitrypsin is deficient in some patients because of a genetic defect, and this leads to a rare form of very severe emphysema in young subjects. Intra-thoracic airways receive collapsing transmural pressures during expiration, whereas extra-thoracic airways receive collapsing pressures during inspiration (Figure 3.5). Recognising the obstructive ventilatory defect in clinical practice Whilst increased airway resistance is the fundamental lung measurement of the obstructive ventilatory defect, it is difficult to measure. Therefore in clinical practice it is more usual to rely on spirometry (record of the forced expiratory manoeuvre) (Figure 2.11). The FEV1 is reduced below 80 % predicted; the FVC is also reduced depending on the severity of the obstruction but not as much as the FEV1, so that the FEV1/FVC ratio is reduced below the lower limit of normal. A rule of thumb for the normal FEV1/FVC ratio is 0.70 -1 (this rule is not sufficiently precise for the elderly). If lung volumes are also measured, the FRC is increased (hyperinflation). The patient breathes at increased volumes. The increased stretch of the alveolar walls helps open the airways. Chapter 3 Page 20 Airways: obstructive ventilatory defects © Dr JP Jamison Other aspects of airways The airways contribute to dead space, which is the volume in the lungs where no gas exchange can take place. Defence The airways make important contributions to protecting the delicate alveoli, by warming and moistening the inhaled air and by protecting from inhaled foreign material. Particle trapping and removal by the mucociliary escalator (Figures 3.8, 3.9 and 3.10) and coughing is their principal method of removal from the airways. In the alveoli there are macrophages which may engulf foreign material and either move to the airways or return to the lung tissue. There are no lymphatics in alveolar wall but the bronchial walls nearby have lymphatics by which alveolar macrophages can enter the lymphatic system. Non-specific inflammatory defence mechanisms are available. IgA is abundant in bronchial secretions. Specific IgE may be released in the tissues in allergic conditions leading to mediator release and asthma. Figure 3.8 Epithelia Stratified squamous Olefactory Pseudostratified ciliated columnar Simple columnar Simple cuboidal Squamous Figure 3.9 The respiratory epithelium: pseudostratified ciliated columnar Chapter 3 Page 21 Airways: obstructive ventilatory defects © Dr JP Jamison Figure 3.10 Bronchial wall: cartilage, smooth muscle, acini of mucous and serous glands, epithelium Some drugs in asthma/chronic obstructive pulmonary disease (COPD) Therapeutics is not part of this module but some information is included here to assist your integration of learning. 1. 2 agonists Asthma may sometimes be distinguished from COPD by the reversibility of the airway obstruction (increased airway resistance). A 2 agonist such as salbutamol is given by nebuliser and tests of relief of airway obstruction carried out after 15 minutes. Asthmatic airway obstruction should usually reverse, while COPD often does not. In treatment, these drugs are known as bronchodilators or relievers. They act by combining with the 2 receptors on the smooth muscle increasing intracellular cyclic adenosine monophosphate (cAMP) (second messenger), which relaxes the smooth muscle. There are long acting 2 agonists (salmeterol) which bind tightly to exo-sites (adjacent to the 2 receptor) which prolong their action to 12 hours. Side effects of 2 agonists include tachycardia, tremor and hypokalaemia. Administration of a -blocker will exacerbate asthma. 2. Xanthines This group of drugs inhibit the phosphodiesterase enzyme. In theory the intracellular cAMP level is thereby elevated, achieving relaxation. However it has therefore been suggested that the other actions of this group of drugs are important. These include: suppression of mediator release, enhancement of mucociliary transport, decreased pulmonary oedema, decreased pulmonary arterial pressure, increased ejection fraction from the right ventricle, increased strength of diaphragmatic contraction and stimulation of ventilation. The latter actions may be helpful in severe disease. Despite the anti- inflammatory actions, these drugs are primarily considered to be relievers rather than preventers of an asthmatic attack. Theopylline is given orally. Aminophylline is given by slow intravenous injection, but carries dangerous risk. Side effects are common because of the narrow therapeutic window. Nausea, arrhythmias and fits may occur. 3. Muscarinic antagonists Removal of the bronchomotor tone induced by parasympathetic nerves gives potential bronchodilator relief even in COPD. Ipratropium bromide, an atropine derivative, is given by inhalation. It is generally very well tolerated, being less liable than the 2 agonists to cause tachycardia. Chapter 3 Page 22 Gas transport by blood © Dr JP Jamison 4a. Gas transport by blood Cyanosis This term refers to a blue appearance of blood in the circulation as observed through the skin and mucous membranes. It is visible when there is 20-30 g/L reduced (deoxy-) haemoglobin in the blood. Cyanosis may be central cyanosis in which the peripheries and the tongue are blue, or peripheral cyanosis in which only the peripheries, fingers and toes are blue (Figure 4.1). After this chapter you should understand how these clinical signs may arise and therefore the diagnoses they suggest. Figure 4.1 Peripheral and central cyanosis (photographic simulation) Peripheral Central SOME TERMS EXPLAINED In clinical practice you will be frequently required to interpret the partial pressures of oxygen and carbon dioxide in samples of systemic arterial blood. These measurements are critical to understanding respiratory function in health and disease. It is therefore important that you know how the term partial pressure is used and how it relates to the gas content in blood. Partial pressure of a gas in a mixture of gases is the pressure exerted by that gas. It is proportional to the fractional concentration of the gas present. Partial pressure of a gas in solution is the partial pressure which would be required in the gaseous phase to equilibrate with the gas in solution (Figure 4.2). It is proportional to the concentration in simple physical solution. Partial pressures can therefore be used to determine the direction and magnitude of the gradient for diffusion within and between phases. Figure 4.2 ‘Partial pressure of a gas in solution’ Gas mixture Partial pressure in gaseous phase Equilibrium = Water with ‘Partial pressure of gas dissolved gas in solution’ Gas content in blood is the amount of gas present per unit volume of blood (mL/L). Note that this is very different from partial pressure (mmHg or kPa). The relationships between partial pressure and gas content are shown in Figure 4.3 Figure 4.3 Dissociation curves for oxygen (left) and carbon dioxide (right) 500 O2 content CO2 mL/L content mL/L 200 40 100 40 PO2 mmHg PCO2 mmHg Chapter 4 Page 23 Gas transport by blood © Dr JP Jamison Hypoxia: reduced supply of oxygen to tissues Hypoxic hypoxia: reduced partial pressure of oxygen in arterial blood Anaemic hypoxia: reduced oxygen content of blood because of reduced haemoglobin concentration Stagnant hypoxia: reduced supply of oxygen to tissues because of reduced blood flow to tissues Histoxic hypoxia: inability of tissues to utilise oxygen eg enzyme poison Hypercapnia: increased partial pressure of carbon dioxide in arterial blood Hypocapnia: decreased partial pressure of carbon dioxide in arterial blood Hyperventilation: ventilatory minute volume which causes hypocapnia Hypoventilation: ventilatory minute volume which causes hypercapnia Cyanosis: Blue discoloration due to excessive deoxyhaemoglobin (> ~20 g/L), more easily seen in polycythaemia than in anaemia Central cyanosis: seen in the mucosa as well as peripheries: desaturated systemic arterial blood Peripheral cyanosis: seen in peripheries, eg finger tips, but not centrally: arterial blood is saturated but becomes excessively desaturated after tissue extraction, due to poor blood flow. Oxygen saturation: oxygenated haemoglobin as percentage of total haemoglobin. Pulse oximetry: a convenient non-invasive technique for recording the percentage saturation (colour) of arterial (pulsatile) blood with oxygen. (SpO2.or SaO2). Journey of the respiratory gases Oxygen’s journey from the atmosphere to the tissues and the reverse journey for carbon dioxide are illustrated in Figures 4.4, 4.5 and 4.6. You should familiarise yourself with the terms used to describe the various stages of the journey and be able to compare and contrast the two respiratory gases. The numerical data (Figure 4.5) are important and should be memorised in kPa (SI unit in UK) and/or mmHg (USA and many textbooks). The values given are typical normal values but there is a normal range. Figure 4.4 shows the steps or stages in the journey. Ventilation is the process by which the gases move between the atmosphere and the alveoli. Transfer (sometimes called diffusion) is the process by which gases move between the alveoli and the blood in the pulmonary capillaries. Transport is the carriage by blood flow between the lungs and the tissues. Gas exchange in the tissues is the process by which the gases move between the blood in the systemic capillaries and the systemic tissue cells. You should appreciate that the journey is downhill ie down a partial pressure gradient at every stage (Figure 4.6). Abbreviations P Partial pressure C Content A Alveoli a Arterial 𝑣̅ mixed venous Figure 4.4 Steps in the journey of oxygen from the atmosphere to the tissues VENTILATION TRANSFER TRANSPORT GAS EXCHANGE IN TISSUES Chapter 4 Page 24 Gas transport by blood © Dr JP Jamison Figure 4.5 Typical normal partial pressures (and gas contents in blood). P partial pressure; C content; A alveoli; a systemic arterial blood; 𝑣 mixed venous blood. PatmosO2 = 150 mmHg, 20 kPa PatmosCO2 ≈ 0 PAO2 = 100 mmHg, 13.3 kPa PACO2= 40 mmHg,5.4kPa PvO2 = 40 mmHg, 5.4 kPa CvO2 = 150 ml/L PaO2 = 95 mmHg, 12.7 kPa CaO2 = 200 ml/L PvCO2 = 46 mmHg, 6.1 kPa CvCO2 = 525 mL/L PaCO2 = 40 mmHg, 5.4 kPa CaCO2 = 480 mL/L Figure 4.6 The gas cascades. The movement is down a partial pressure gradient at every step. 20 Partial Ventilation Transfer Transport Pressure Gas exchange in tissues kPa 0 Oxygen carriage by blood Understanding the carriage of oxygen by blood flow between the lungs and the tissues requires an understanding of (1) how much oxygen is carried and extracted from each litre of blood (2) the rate of blood flow ie how many litres of blood flow each minute (Figure 4.7). Figure 4.7 Summary of delivery of oxygen to tissues at rest. Oxygen uptake at mouth equals oxygen consumption by tissues in steady state. Arteriovenous difference is also known as oxygen extraction. cardiac output 1 L blood 5 L/min in systemic artery in mixed venous blood 200 150 mL O2/L mL O2/L O2 250 mL/min oxygen uptake or consumption Oxygen uptake = arteriovenous difference in oxygen content × cardiac output Chapter 4 Page 25 Gas transport by blood © Dr JP Jamison Oxygen in blood Oxygen is largely carried in blood by a loose ssociation with haemoglobin. Haemoglobin structure is shown in Figures 4.8 and 4.9. Figure 4.8 The haem and globin components of the haemoglobin molecule O2 Porphyrin ring Haem N N Fe++ N N Globin Figure 4.9 Comparison of adult and fetal haemoglobin. There are 4 subunits in each haemoglobin molecule. The four O2 molecules associate with the four haem components. The fetal haemoglobin has the same haem moieties but two different globin components. Although not directly attached to oxygen, the globin component affects the affinity of the haemoglobin for oxygen. Fetal haemoglobin has increased affinity but the same capacity for oxygen as maternal haemoglobin. Maternal Fetal O2 O2 O2 O2     g    g  O2 O2 O2 O2 The oxyhaemoglobin dissociation curve The plot of O2 content against PO2 to which the blood has been equilibrated (Figure 4.10) is the best description of how oxygen is carried by blood and is essential to the understanding of many clinical observations and conditions: respiratory, haematological and circulatory. There is a plateau of maximum oxygen content, called the oxygen capacity. On the plateau, there is little increase in oxygen content with increasing partial pressure. The reason is that there is a limited number of binding sites for oxygen. When all binding sites are full no more oxygen can be added to the haemoglobin. The plateau is not absolutely flat because there is a small continuing increase in dissolved oxygen at higher partial pressures. There is a foot to the curve. This is caused by increasing affinity for oxygen after the first oxygen molecules bind to the haemoglobin. The partial pressure at which 50 % of the binding sites are occupied, which determines the position of the steep part of the curve can be used as a measure of oxygen affinity. This position shifts to the right in venous blood (Figure 4.10). Note there are two scales used for oxygen content – the absolute content as mL O2 at STP per L of blood; and percentage saturation, where the plateau, irrespective of the absolute content, is called 100 %. Measurement of percentage saturation of arterial blood is commonly measured in clinical practice. The equipment is a pulse oximeter. It measures the absorption of light of the appropriate wave length to detect the proportion of the total haemoglobin which is oxyhaemoglobin (red). (De-oxyhaemoglobin is blue.) The pulse oximeter is used non-invasively from the skin surface Chapter 4 Page 26 Gas transport by blood © Dr JP Jamison and arterial blood is distinguished from capillary and venous blood by the pulsing of arterial blood. Normal saturation by pulse oximetry is 96-100 %. Figure 4.10 The oxygen-haemogobin dissociation curve: oxygen content when the blood is equilibrated to various partial pressures of oxygen. The content scale is shown both as absolute content and as percentage saturation, where the plateau is called 100% saturated. The oxygen capacity is the high plateau. The affinity is the location of the steep part of the curve. The affinity is affected by the environment of the haemoglobin: venous blood has a lower affinity (blue) than arterial blood (red), though its capacity is identical (Bohr shift). The dissolved oxygen is shown in green. Although the amount dissolved is quite small it is important as its concentration is proportional to the partial pressure and gives rise to the concentration gradients to drive diffusion across capillary walls in the lungs and systemic tissues. % saturation 200 100 mL/L Normal point 80 in systemic arteries 150 Normal point Arterial blood 60 in mixed venous blood Venous blood with subject at rest Dissolved Oxygen content Bohr shift to right 40 ↑ PCO2 ↑ temperature ↑ H+ 20 ↑ 2,3 diphosphoglycerate 0 0 0 20 40 60 80 100 mmHg 0 5 13 kPa Partial pressure of Oxygen There are other oxygen binding molecules – myoglobin and fetal haemoglobin. The affinities of these are to the left of adult haemoglobin (Figure 4.11). Figure 4.11 The myoglobin and fetal haemoglobin dissociation curve are shifted to the left ie have higher affinity for oxygen than adult haemoglobin. % saturation 100 80 60 Oxygen content Haemoglobin 40 Myoglobin/ fetal haemoglobin 20 0 0 20 40 60 80 100 mmHg Chapter 4 Page 27 Gas transport by blood © Dr JP Jamison Anaemia is a lower than normal haemoglobin concentration in peripheral blood. The dissociation curve is shifted downwards but this is not apparent with the percentage saturation scale (Figure 4.12). Figure 4.12 Anaemia reduces the oxygen capacity (green scale and green curve) but this is not apparent if the % saturation scale is used (red scale and red curve); there may be a slight Bohr shift. Hypoxia This refers to a shortfall in the supply of oxygen for metabolism. There are 4 causes. Hypoxic hypoxia: lower PaO2: this is respiratory – reduced ventilation and/or transfer or reduced inhaled O2 (↓fractional inhaled oxygen, FIO2). Anaemic hypoxia: lower oxygen content due to reduced haemoglobin, PaO2 is normal, SpO2 (pulse oximetry) are normal. Stagnant hypoxia: reduced blood flow eg heart failure. Histoxic hypoxia: tissues are unable to use the oxygen eg metabolic poison Chapter 4 Page 28 Carbon dioxide transport by blood © Dr J P Jamison 4b. Carbon dioxide transport by blood Role of CO2 in acid base balance Carbon dioxide reacts with water to produce carbonic acid. This is a weak acid and therefore acts as a buffer. The defence of the H+ concentration in the body depends on the following: buffers, respiratory regulation, renal regulation. These defences are mobilised in that order. Buffer action (Figures 4b.1, 4b.2) is immediate, respiratory regulation in minutes, renal regulation takes days to weeks. Figure 4b.1 Buffer action is best at a pH equal to the pK of the buffer HA H+ + A─ pH [HA] [H+] = k [A─] pH = pk [A─] pH = pk + log [HA]{ } ←Acid added Alkali added→ Figure 4b.2 Two buffers. Haemoglobin is the best as a buffer in blood, but carbonic acid has physiological importance because of its interaction with the lungs and kidneys Introduction to acid/base diagnoses You will be required to diagnose the acid/base status from arterial blood analysis data. The following bullet points are a start. The normal pH is 7.4 and the acceptable range is quite tight (±0.05). The pH is lowered in acidosis and elevated in alkalosis. Then consider whether the cause of a disturbance of pH is respiratory or non-respiratory. The respiratory system has only one acid to excrete, though in large amount – carbonic acid. If the respiratory system is responsible for acidosis, then the carbonic acid level will be too high, reflected in a high PaCO2. If an acidosis is due to a non-respiratory cause then the PaCO2 is actually low as the respiratory system blows off more CO2 to compensate for the other acid. This condition can be called non-respiratory acidosis but more usually it is called metabolic acidosis. Alkalosis is diagnosed in a similar way, by the opposite changes. Chapter 4 Page 29 Carbon dioxide transport by blood © Dr J P Jamison Normal pH is 7.4 Acidosis is pH < 7.35 Alkalosis is pH > 7.45 Respiratory acidosis is retention of carbonic acid - ↑PCO2 - may be acute or chronic Non-respiratory (metabolic) acidosis is increased non-carbonic acids - ↓PCO2, ↓HCO3─ The CO2 dissociation curve This is the relationship between CO2 content of blood when equilibrated at various PCO2. Firstly the physiologically significant values are shown in Figure 4b.3. Figure 4b.3 CO2 in arterial and mixed venous blood, compared with O2 (abbreviations as before) PatmosO2 = 150 mmHg, 20 kPa PatmosCO2 ≈ 0 PAO2 = 100 mmHg, 13.3 kPa PACO2= 40 mmHg,5.4kPa PvO2 = 40 mmHg, 5.4 kPa PvCO2 = 46 mmHg, 6.1 kPa PaO2 = 95 mmHg, 12.7 kPa CvCO2 = 525 mL/L PaCO2 = 40 mmHg, 5.4 kPa CaCO2 = 480 mL/L The partial pressure of CO2 in systemic arterial blood is typically 40 mmHg (5.4 kPa), and 46 mmHg (6.1kPa) in mixed venous blood at rest. The contents are 480 mL/L and 525 mL/L respectively. Note that there is more than twice as much CO2 in blood as O2. Although the difference in CO2 content between the arterial and venous bloods is similar to (slightly less) the arterio-venous difference for O2, the difference in partial pressures is much less for CO 2. Figure 4b.4 The CO2 dissociation curve 700 Haldane effect Normal point in mixed venous blood ↓ PO2 600 Carbon dioxide 500 content mL/L 400 Arterial blood Normal point in Venous blood 300 arterial blood Dissolved 200 100 0 0 10 20 30 40 50 60 70 80 mmHg 0 5 6 8 kPa Partial pressure of carbon dioxide The CO2 dissociation curve (Figure 4b.4) is simpler than the O2 dissociation curve. In the physiological range it is close to a straight line. Over more extreme PCO2 changes there is a slight curve. Unlike the curve for O2, there is no plateau. The reason for this difference is that CO2 reacts Chapter 4 Page 30 Carbon dioxide transport by blood © Dr J P Jamison mostly with water, of which there is effectively an unused large supply, while O2 reacts with haemoglobin which has a rather limited number of binding sites which are filled up (saturated) at physiological PO2. Another difference is that the CO2 is 23 times as soluble as O2, so the line for dissolved CO2 (green line) is steeper than for O2. There is a shift of the curve between arterial (red line) and venous (blue line) blood. Venous blood can take up more CO2 than arterial blood for any given PCO2. This is called the Haldane effect. It is larger than the Bohr shift of the O2 dissociation curve. It enables venous blood to pick up CO2 more readily. As the CO2 curve itself is very steep and is effectively steepened further by the Haldane effect, a very small change in PCO2 is needed to add 45 mL/L CO2 to the blood in the tissues and vice versa in the lungs. CO2 does not react with the haem moiety of haemoglobin. It reacts with the globin component to form carbamino haemoglobin. This accounts for a small proportion of the CO2 in blood (~10 %). Texts often quote >20 %. This is too high because the very slow rate of reaction of CO2 with haemoglobin means that the reaction does not proceed to equilibrium in the circulation. In summary, CO2 is carried in blood in three ways: dissolved (10%), reacted with globin to become carbamino haemoglobin (10%) and reacted with water to become HCO 3- (80%) (Figure 4b.5). Plasma carries 70 % of the CO2 because there is more water in plasma than in red cells. However the reactions occur inside the red cells (Figure 4b.6). Very much smaller pressure gradients are needed to move CO2 in and out of blood than are needed for O2. Figure 4b.5 The distribution of CO2 in blood Carbamino compounds 10% Red blood cells Dissolved CO2 30% 10% Plasma HCO3─ 70% 80% Figure 4b.6 The reactions of CO2 inside red cells The reason that the reactions of CO2 occur inside red cells is the reactions are too slow to be effective in the plasma – the time available in a capillary is less than a second. Inside the red cells there is an enzyme carbonic anhydrase which catalyses the reaction of CO2 with water. In the lungs, the HCO3- ions produced diffuse out into the plasma, so the plasma contributes to the carriage of CO 2 and allows the reaction to proceed further inside the red cell rather than being inhibited by increased HCO3-. The Cl- ions diffuse in from the plasma to preserve electrical neutrality (chloride shift). The H+ ions Chapter 4 Page 31 Carbon dioxide transport by blood © Dr J P Jamison produced by the reaction of CO2 with water are buffered by the haemoglobin. This is the best buffer in blood and is immediately available inside the red cells. Furthermore de-oxyhaemoglobin is a better buffer than oxyhaemoglobin. This helps explain the Haldane effect. Venous blood, with more de- oxyhaemoglobin, takes up more CO2 partly because of the better buffering of the H+. The formation of carbamino haemoglobin also contributes to the Haldane effect. Carbon dioxide output At rest the volume of carbon dioxide output per minute is slightly less than the volume of oxygen consumed per minute, the ratio being called the respiratory exchange ratio (R). Acid/base diagnosis There are various acid/base diagrams. The Flenley version (Figure 4b.7) is very helpful. It is a plot of pH against PCO2 for samples of arterial blood. These two parameters are measured in the biochemistry lab by pH and PCO2 sensitive electrodes. Bicarbonate (HCO3-) is also relevant but is calculated from the pH and PCO2 by the Henderson Hasselbach equation (Figure 4b.2). Figure 4b.7 Flenley acid base diagram. This diagram is not included in module examination questions but is included here for future reference in clinical practice. Acid/base problems will be included in the module examination. The central box gives the normal ranges. Data lying within the marked zones indicate the diagnosis as labelled. If data lie outside these zones then there is a mixed acid base disturbance. Try to diagnose the cases A-G. Acid/base will be re-considered with the renal system. A B C D E F G pH 7.4 7.2 7.3 7.2 7.6 7.45 7.1 PaCO2 5.4 8.5 8.5 4.0 3.5 3.5 7.0 kPa HCO3─ 25 26 31 12 24 18 16 mmol/L Chapter 4 Page 32 Transfer: alveolo-capillary membrane © Dr J P Jamison 5. Transfer of gases across the alveolo- capillary membrane Amount of gas transfer At rest the volume of oxygen transferred from the alveoli to the pulmonary capillaries is about 250 mL/min. This is called the rate of oxygen consumption or oxygen uptake if measured at the mouth. The oxygen content of mixed venous (pulmonary arterial) blood is 150 mL O2/L of blood. The lungs add 50 mL of oxygen to each litre of blood, so pulmonary venous (systemic arterial) blood contains 200 mL O2/L of blood. There is a flow of 5 L blood through the pulmonary capillaries each minute. Thus 250 mL O2 is taken up by the lungs each minute (5×50=250). A little less carbon dioxide is transferred in the opposite direction (R 2mm diameter by infection. The dilatations can be cylindrical, varicose or cystic. Transmural inflammation weakens the muscle and elastic tissue of the bronchial wall allowing parenchymal traction to dilate the affected segment. The flabby wall also collapses during expiration and clearance of secretions is impaired. There is usually an obstructive ventilatory defect with wheeze. The inadequate clearance of secretions allows micro-organisms to grow causing on-going infection and stimulation of excessive secretions. The principle characteristic symptom of bronchiectasis is therefore large amounts of muco-purulent sputum. Purulence may be recognised by discoloration or odour of the sputum. There can be occasional haemoptysis. Bronchiectasis is more common in gammaglobulin deficiency, ciliary dskinesia and in cystic fibrosis because of the increased prevalence of infection. In cystic fibrosis, a genetic defect impairs chloride secretion which affects sodium and water resorption, dehydrating mucosal secretions and rendering the mucus viscid and hard for the cilia to clear. Stasis of the secretions allows micro-organisms to grow. Spirometry usually shows obstruction. The dilated bronchi with thickened walls can be seen on chest X-ray or CT scan (Figure 7.8). Chapter 7 Page 50 Pathophysiologies © Dr J P Jamison Figure 7.8 CT scan of right lung showing varicose bronchiectasis Chapter 7 Page 51 Pathophysiologies © Dr J P Jamison Respiratory Failure – notes only Definitions Partial pressure of oxygen in arterial blood lower than 60 mmHg (8 kPa) not due to some other cause (eg high altitude, right to left cardiac shunt etc). Type 1 - As above without hypercapnia Type 2 - Hypoxia as above plus partial pressure of carbon dioxide in arterial blood higher than 45 mmHg (6 kPa) Causes NEUROMUSCULA R TYPE 2 VENTILATION RESPIRATORY ABNORMALITY FAILURE (HYPERCAPNIC) LUNG LOAD ON WORK OF FATIGUE COMPLIANCE BREATHING BREATHING AWR CHEST WALL ABNORMALITY WASTED VENTILATION DEAD SPACE ALVEOLO-CAPILLARY MEMBRANE DISORDERS TYPE 1 ABNORMAL GAS RESPIRATORY V/Q MISMATCH TRANSFER FAILURE (NORMOCAPNIC) SHUNTS Effects of hypoxia BLOOD Central cyanosis, polycythaemia BRAIN Visual impairment, restlessness, irritability, poor sleep at night, daytime sleepiness, confusion, convulsions, coma, death LUNGS Dyspnoea, pulmonary vasoconstriction, increased pulmonary vascular resistance (hypoxic vasoconstriction plus hyperviscosity due to polycythaemia), pulmonary hypertension. Worst during exercise. HEART Right ventricular strain caused by pulmonary hypertension, right ventricular hypertrophy, right ventricular dilatation, right ventricular failure, dilatation of valve rings, pulmonary valve incompetence, tricuspid incompetence, tachycardia, arrhythmias. Elevated central venous pressure (JVP), increased pulse waves in JVP, leg and sacral oedema, (liver and peritoneal cavity and other organs eg kidney can also be affected) Effects of hypercapnia BRAIN Vasodilatation, increased cerebral blood flow, increased cerebrospinal fluid pressure, cerebral oedema, papilloedema, headache on waking, drowsiness, flapping tremor, muscle twitching GENERAL Direct action is to cause peripheral vasodilatation, warm peripheries, SYSTEMIC dilated veins, increased pulse pressure, eventually decreased arterial blood pressure CIRCULATION Reflex action via chemoreceptors and sympathetic stimulation is peripheral vasoconstriction, pale, cold and clammy (sweaty) skin. There may be a mixture of the above influences. Tendency for reflex to be more prominent acutely and direct action more more prominent in chronic respiratory failure (reflex adapts) RESPIRATORY Dyspnoea, sense of suffocation, increased ventilation if SYSTEM possible, loss of sensitivity to carbon dioxide in chronic hypercapnia. Clinical syndromes often due to chronic obstructive pulmonary disease (terms are rather out-dated) Blue bloater: Cyanosed, peripheral oedema due to cor pulmonale (right ventricular failure due to lung disease). Blood gases show respiratory failure. Ventilatory response to hypercapnia is reduced. Oxygen therapy causes further hypercapnia. Pink puffer: Dyspnoeic. May breathe with pursed lips. Maintain blood gases until terminal illness. Ventilatory response to hypercapnia is good. Significance is that, despite good blood gases, pulmonary function shows serious loss of reserve. When these patients go into respiratory failure they die very soon thereafter. Chapter 7 Page 52  © Dr J P Jamison Pulmonary function tests – for cross referencing with tutorials, practicals and clinical practice Tests of Lung mechanics Peak expiratory flow rate Peak inspiratory flow rate Forced expiratory manoeuvre (spirometry) Forced expiratory volume in first second (FEV 1) Forced vital capacity (FVC) Measurement of the FEV1 and FVC is the most useful single test of lung function. Using it, diseases of the lung can be divided into diseases of the airways - seen as the obstructive ventilatory defect (decreased FEV1, FVC and FEV1/FVC ratio) and diseases of the alveoli - seen as the restrictive ventilatory defect (decreased FEV1 and FVC with no change or increase in the FEV1/FVC ratio) (note that it is the lung volumes that are "restricted") Reversibilty of obstructive ventilatory defect using a 2 agonist very useful to confirm asthma and determine appropriate treatment Responsiveness using methacholine – useful to detect asthma between attacks Allergen challenge Flow/volume loops useful to assess small airway obstruction and to distinguish between intrathoracic and extrathoracic airway obstruction Lung volumes Tidal volume Inspiratory reserve volume Expiratory reserve volume Vital capacity Inspiratory capacity Residual volume Functional residual capacity Total lung capacity Minute volume = tidal volume × respiratory frequency Alveolar minute volume = (tidal volume-dead space) × respiratory frequency Compliance Useful but too uncomfortable to use often in practice Airway resistance Useful because it clearly separates the airways from the alveoli, but expensive and difficult Closing volume rarely measured, but the phenomenon has clinical importance, especially in anaesthesia Dead space rarely measured, but is of fundamental importance Maximal expiratory/inspiratory pressures Useful for testing strength of respiratory muscles Tests of Gas Transfer (Diffusing capacity) Carbon monoxide transfer test Effect of oxygen Effect of allergen challenge Tests on blood Arterial blood gases and pH Alveolo-arterial partial pressure differences Haemoglobin % saturation with oxygen (pulse oximeter) Exercise testing Useful to detect early disease, to determine cause of exercise limitation (cardiac v pulmonary) and to help determine level of disability. Normal reference ranges for lung function These are determined by measuring a random sample of healthy people of a range of ages and heights, both sexes. The average for an individual of a particular age sex and height is referred to as the predicted value. Percentage predicted is actual value divided by the predicted value and multiplied by 100. The normal range ’rule of thumb’ is