Lung function tests (LFTs) and arterial blood gas measurements (ABGs) are an important part of everyday clinical practice, especially in cardiorespiratory medicine. Their principal clinical uses are in:
- Diagnosing respiratory and cardiac disease
- Assessing the severity of acute disease (e.g. chronic obstructive pulmonary disease, COPD) and acute-on-chronic disease (acute exacerbation of a chronic disease, e.g. muscular dystrophy)
- Predicting the prognosis of chronic lung diseases (e.g. to assist decisions about lung transplants in patients with COPD or cystic fibrosis)
- Measuring the response to management (e.g. the efficacy of steroid inhalers in asthma)
- Preoperative safety checks
- Postoperative and critical care monitoring
The assessment of lung function provides vital information, especially when the signs and symptoms of lung disease are subclinical. Respiratory function may be severely impaired even if the lungs appear normal on a chest radiograph. Conversely, gross radiological abnormalities may be associated with only mild impairment of physiological function.
The lungs are divided into lobes, which themselves are separated by fissures (Figure 1.1). The right lung has three lobes: upper, middle and lower. In contrast, the left lung has only two lobes: upper and lower. The left upper lobe is subdivided into an upper lobe corresponding anatomically to the right upper lobe and the lingular lobe, which is analogous to the right middle lobe; there is no fissure between these two.
The bronchial tree starts at the division of the trachea into right and left main bronchi (Figure 1.2). It divides up to twenty-eight times from the trachea to the alveoli, the site of gas exchange between the air and the blood:
- Main bronchi, left and right
- Lobar bronchi, each supplying a lobe of the lung
- Segmental bronchi, each supplying air to a bronchopulmonary segment (see below and Figure 1.3)
- Lobular bronchi
- Conducting bronchioles
- Terminal bronchioles
- Respiratory bronchioles
- Alveolar ducts
- Alveolar sacs
The trachea and bronchi act as a pathway for air entering and leaving the lungs. They have no function in gas exchange but mucocilliary clearance takes place for the purpose of preventing infection.
Each lobe is subdivided into a number of bronchopulmonary segments (Figure 1.3). A bronchopulmonary segment is an anatomically and functionally discrete unit with respect to both respiration and circulation: as well as having by its own bronchiole, it is supplied by its own artery. There are ten segments in the right lung and eight in the left with twenty-three generations of airways in total.
Each bronchopulmonary segment is anatomically divided into subsegments of various orders, down to the level of the respiratory lobule (Figure 1.4). The lobule consists of a terminal bronchiole and its divisions, leading to alveolar ducts which terminate in alveolar sacs.
Figure 1.3: Bronchopulmonary segments of the lung. (a) Lateral view. (b) Medial view. Oblique fissures; horizontal fissures.
The alveolar sac is a collection of alveoli separated partially or completely by connective tissue which contains blood vessels, lymphatics and nerves. The alveolar walls are lined by flat squamous epithelial cells on a basement membrane. The alveolar wall is the site of gas exchange: diffusion between alveoli and capillary vessels. It is a component of the respiratory membrane, which has a structure that optimises gas exchange (Figure 1.5):
- fluid/surfactant (keeping the alveoli patent)
- alveolar epithelial cells (95% are type I pneumocytes)
- basement membrane (made of structural network proteins)
- interstitial space
- capillary endothelial cells
The basement membrane itself is extremely thin (averaging 0.5 µm). Across roughly 700 million alveoli a person has a total respiratory membrane of 50–75 m2.
Figure 1.5: The alveolar wall. Two alveoli are shown here, with an interconnecting pore between them. The pores develop in the early years of life, allowing collateral ventilation but also serving as a route for infection.
During normal inspiration, about two-thirds of the inhaled air enters the alveoli; the rest remains in the ‘anatomical dead space’ of the conducting airways.
The pulmonary circulation is unique in that the pulmonary artery carries deoxygenated blood to the lungs and the pulmonary vein carries oxygenated blood from the lungs to the heart.
The lungs are supplied by two sets of arteries, each with distinct roles:
- Pulmonary arteries carry blood from the right ventricle of the heart to the alveoli, where it receives oxygen
- Bronchial arteries originate from the thoracic aorta and supply oxygenated blood to the tissues of the lung
Pulmonary arteries accompany the bronchi, terminating in the pulmonary arterioles (see Figure 1.4). These divide into dense capillary networks closely surrounding the alveolar walls. Bronchial arteries are relatively small and accompany the divisions of the bronchi.
The pulmonary veins arise chiefly as venules in the alveolar capillary network and, to a lesser extent, from other parts of the respiratory lobule and pleurae. The venules drain into larger branches that follow a course independent of the bronchi and arteries; and are generally intersegmental. They finally form the four pulmonary veins (two from each lung) that empty oxygen-rich blood into the left atrium of the heart.
Most of the deoxygenated blood from lung tissue itself returns to the heart via pulmonary veins. Less than 15% drains via the bronchial veins into the azygous and hemiazygous veins and then into the systemic circulation.
Respiration encompasses three processes:
- Ventilation: the drawing in of atmospheric air to reach the alveoli (inspiration) and the removal of gases back to the atmosphere (expiration)
- Gas exchange between the alveoli and alveolar capillaries, with oxygen (O2) entering the blood from the alveoli and carbon dioxide (CO2) being excreted from the blood into the alveoli
- Gas exchange between the systemic circulation and the tissues and cells it supplies
The purpose of the lungs is to facilitate ventilation and provide a large surface area for gas exchange between the alveoli and capillaries. Anything that reduces ventilation, the surface area or blood flow through the alveolar capillaries will reduce gas exchange in the alveoli.
1.3 Ventilation and lung volumes
Normal ventilation depends on:
- an intact neuromuscular mechanism (see )
- the lungs, pleurae and thoracic cavity expanding and contracting to fully allow the inspiration and expiration of air (Figure 1.6)
- compliant lungs
- patent airways
The ability of the lungs to stretch in response to a change in pressure is termed lung compliance and is dependent on the elastic properties of the lungs and elastic forces in the thorax. Lung diseases can impair ventilation and increase the work required to breathe by increasing or decreasing lung compliance.
Figure 1.6: The mechanism of ventilation. The intercostal muscles and diaphragm contract, increasing the size of the thoracic cavity and drawing air into the lungs. Relaxation of the muscles and the elastic recoil of the chest wall reduce the size of the thoracic cavity and forcing air out of the lungs.
The measurements of lung volume are shown in Figure 1.7.
At rest, a healthy individual breathes in or out around 400 mL air with each breath; this is the tidal volume (VT). Over and above this tidal volume, an additional amount of about 2800 mL air can be breathed in by maximum effort; this is the inspiratory reserve volume (IRV). The sum total of tidal volume and inspiratory reserve volume, about 3200 mL, is the inspiratory capacity (IC).
The IRV is a measure of the reserve available to the individual for an increase in tidal volume during exercise. Similarly, after a normal expiration of tidal volume, it is possible to breathe out an amount of air equal to about 800 mL by maximal expiration called the expiratory reserve volume (ERV).
Figure 1.7: Lung volumes. ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV, inspiratory reserve volume; ERV, expiratory reserve volume; RV, residual volume; TLC, total lung capacity; VT, tidal volume; VC, vital capacity.
Vital capacity (VC) is the maximum volume of air that can be breathed out after a maximal inspiration. In healthy individuals the VC is about 4000 mL. This is discussed further in Chapter 2.
About 1000 mL of air remains inside the lungs even at the end of maximal expiration because of negative intrathoracic pressure. This so-called dead space is termed the residual volume (RV). It is calculated by deducting the expiratory reserve volume (ERV) from the functional residual capacity (FRC). FRC is the amount of air remaining in the lungs (especially in the parenchyma) after a passive expiration. So:
The total lung capacity (TLC) is the total volume of gas contained in the lungs at the end of maximal inspiration:
TLC = VC + RV
TLC is about 5 L in a healthy adult.
A mechanical effort (the ‘work of breathing’) is required to move the lungs and related tissues. The rate and depth of respiration automatically adjust to produce the required alveolar ventilation, whether in a healthy or diseased state. The respiratory rate is usually 10–14 breaths/min in healthy adults.
1.4 Gas exchange in the alveoli
The primary function of the respiratory system is to maintain levels of the respiratory gases O2 and CO2 to ensure:
- O2 supply to all tissues is adequate
- CO2 is excreted before it causes toxicity
Gas levels are expressed as partial pressures (see Box). So this function can be re-described more formally as maintaining the partial pressures of O2 and CO2 in arterial blood (Pao2 and Paco2) within narrow physiological limits suited to the body and its cells (Table 1.1).
O2 and CO2 levels, Pao2 and Paco2, vary throughout the circulatory system as O2 is consumed and CO2 is produced by cellular metabolism. Ordinarily, the rate, depth and rhythm of breathing are adjusted to match the changing needs for O2 uptake and CO2 elimination so that the arterial levels of these gases are maintained within normal limits. The three main factors that are regulated to maintain this balance are:
- Ventilation of the lungs (see above) and alveoli (see below)
- Diffusion, i.e. gas crossing the respiratory membrane – diffusion cannot be regulated directly but the factors affecting diffusion can (e.g. haemoglobin concentration, pulmonary capillary blood volume, transit time)
- Perfusion of the alveoli, i.e. the circulation of blood into and out of the capillaries around the alveoli
These processes are intimately linked, and diseases can affect any or all of them. Consider each process separately when trying to diagnose the cause of a patient's respiratory compromise.
Alveolar ventilation is the amount of air that enters the lungs and reaches the alveoli, and is therefore available for gas exchange. Disorders of alveolar ventilation therefore reduce alveolar gas exchange.
Calculating alveolar ventilation
Alveolar ventilation (V.A) is calculated from
V.A = [tidal volume (mL) – anatomical dead space (mL)] × respiratory rate
= [VT – dead space] × respiratory rate
The anatomical dead space does not take part in gas exchange. In health, it is approximately 180 mL in men and 120 mL in women, thus:
In men: V.A = (tidal volume – 180 mL) × respiratory rate
In women: V.A = (tidal volume – 120 mL) × respiratory rate
On average, alveolar ventilation in healthy adults is about 4 L/min.
In clinical practice, values for alveolar ventilation are difficult to measure because it is impractical to measure O2 and CO2 in exhaled gases at the bedside. Instead, it would be logical to use the partial pressure of alveolar gas (Paco2) as an indirect measure of alveolar ventilation. In practice, however, Paco2 is used because it is easily measured in an arterial blood sample and it is reasonable to assume it is approximately equal to Paco2 because CO2 so easily diffuses across the alveolar membrane.
Influence of alveolar ventilation gas exchange
Alveolar ventilation influences the amount of gas available for exchange at the alveolar wall. The Paco2 is directly related to the amount of CO2 produced by the body per minute (V.co2) (i.e. a rise in V.co2 is associated with a rise in Paco2). Conversely, Paco2 is inversely proportional to alveolar ventilation, since an increase in alveolar ventilation leads to greater removal of CO2 from the alveolus and so consequently:
- When alveolar ventilation increases, the Paco2 falls
- When alveolar ventilation decreases, Paco2 rises, which explains the rise in Paco2 when patients have reduced or impaired ventilation
Distribution of alveolar air
The distribution of inspired gas varies across the alveoli during the normal ventilatory cycle. Therefore, even if alveolar ventilation is normal, full arterial O2 saturation is not maintained. In diseased states, when the anatomy of the lung is markedly uneven, areas of the lung will have a low ventilation–perfusion ratio (see below).
Alveolar gas equation
The partial pressure of oxygen within the alveoli (Pao2), is determined:
- either through laboratory analysis of an end-tidal sample of expired air (a sample of expired gas drawn after the end of either a tidal breath of a forced expiratory manouevre), which is a cumbersome procedure unsuited to clinical situations
- or by calculation from the alveolar gas equation:
where Fio2 is the fraction of inspired air that is oxygen (21%), PATM is the atmospheric pressure (~101 kPa or 760 mmHg at sea level), Ph2o is the pressure of water vapour in air (6.2 kPa or 47 mmHg at 37°C when fully saturated), Paco2 is the arterial pressure of CO2 (used instead of Paco2 – see ) and R is the respiratory quotient
The respiratory quotient is the ratio of CO2 produced by the body's metabolism compared to the O2 consumed, and is therefore a reflection of the fuel being consumed by the body's metabolism. With a normal diet it is almost always around 0.8.
Alveolar–capillary diffusion is the process of gas exchange between the alveoli and the capillary vessels; it is crucial to determining how much O2 reaches the blood.
O2 moves from the alveolar space, through the respiratory membrane and blood plasma, and into the red blood cell by diffusion down its pressure gradient, i.e. from higher to lower Po2. A disturbance in the respiratory membrane may impair oxygen diffusion.
CO2 also diffuses down its pressure gradient, i.e. in the opposite direction, from blood to alveolar air. Because CO2 has a diffusing capacity (Dco2) that is about 20 times greater than that of O2, impairment of its diffusion is rarely of clinical relevance.
Diffusing capacity of O2
The diffusing capacity of O2 capacity (Do2) is a measurement of the ability of the respiratory membrane to transfer O2. It is calculated as the volume of O2 (mL) that diffuses across the alveolar–capillary membrane per minute per kPa pressure difference (i.e. the pressure gradient). In practice, alveolar–capillary diffusion is measured by calculating the resting diffusing capacity of carbon monoxide (see ).
Perfusion – movement of blood into and out of the alveolar capillary network – must be at a level adequate for gas diffusion and transport into the general circulation to meet the body's needs.
Pulmonary blood flow
In a resting healthy adult the right ventricle pumps 5–6 L of blood per minute into the pulmonary circulation, producing a pulmonary arterial pressure of 15–30 mmHg during systole and 5–10 mmHg during diastole. The pulmonary vessels are wide, meaning resistance is only a fifth of that of the systemic circulation. Consequently, during exercise pulmonary vessel blood flow can increase sixfold to about 30 L/min, with only a minimal increase in pressure in healthy individuals.
Any disease which impairs pulmonary blood flow impairs the delivery of oxygen to tissues (see Figure 1.8).
Pulmonary vascular resistance
Pulmonary vascular resistance is the pressure against which blood in the pulmonary circulation has to flow and is obtained from the pulmonary arterial pressure, pulmonary capillary wedge pressure (an estimate of pulmonary capillary bed pressure) and cardiac output. Resistance increases when pulmonary arterial and arteriolar vasoconstriction occurs in alveolar hypoxia and this is also seen in a number of different lung diseases. More prolonged and severe alveolar hypoxia leads to increased resistance and raised pulmonary blood pressure.
Clinical determinants of gas exchange
The three key clinical determinants of gas exchange are:
- Ventilation–perfusion ratio (/)
- Alveolar–arterial oxygen gradient (Pa–ao2)
- Shunt fraction (S/T)
The ventilation–perfusion ratio is the ratio of alveolar ventilation to the alveolar blood flow. It is abbreviated as (
representing volume of air,
representing volume of blood and the dot representing flow. This parameter is useful because anything that reduces ventilation (producing a lowered
ratio) or results in a deficiency of perfusion (giving a raised
ratio) leads to inefficient transfer of oxygen to the blood (Figure 1.8). This causes tissue hypoxia (see ).
ratio is calculated as follows:
The average alveolar ventilation is about 4 L/min and the average normal blood flow through the lungs is about 5 L/min, giving an overall
ratio of 0.8.
ratio varies slightly within the lungs of a healthy adult. The upper lobes are less well ventilated than the lower lobes, because gravity pulls down the weight of lung tissue and slightly restricts the movement of the lower parts of the lung. However, gravity also influences perfusion pressure in the lungs: the lung bases receive significantly more blood than the upper lobes. Together these mean that the
ratio is highest in the upper lobes and lowest in the lower lobes of the lungs.
Alveolar–arterial oxygen gradient
The alveolar–arterial oxygen gradient (Pa–ao2, or a–a gradient) is the difference between the partial pressure of oxygen in the alveoli and the partial pressure of oxygen in the arteries. In a typical individual breathing room air (at Fio2 21%) the Po2 in alveolar air is 13.8 kPa and in arterial blood 12.6 kPa. Pao2 exceeds Pao2 by 2 kPa. Thus, the Pa–ao2 in this case would be 1.2 kPa.
Pa–ao2 is a a useful indicator of pulmonary gas exchange function. A normal A-a gradient requires that three elements are working correctly:
- Circulatory anatomy is normal. Anomalies such as congenital heart defects (e.g. atrial septal defect, patent ductus arteriosus) cause anatomical shunting, i.e. venous blood passes through routes that are not exposed to alveolar air
- Ventilation and perfusion are matched so that ventilated areas of the lung are matched by venous blood perfusion. A mismatch is termed functional shunting in that there is an imbalance between the supply of air and the supply of blood to certain regions of the lungs. For example, collapse of a lung can lead to a region being perfused with blood but not yet ventilated and is therefore tantamount to a shunt. Likewise, pulmonary arterial occlusion will lead to a normally ventilated region not being perfused
- The respiratory membrane allows sufficient free diffusion of gases between air and blood. Diffusion defects impair the alveolar–capillary membrane, e.g. in interstitial lung fibrosis
Real-time measurement of Pa–ao2 requires simultaneous measurement of Pao2 and Pao2. To do this, the end-tidal alveolar Pao2 is measured or calculated (see ) and an arterial blood sample is simultaneously collected for ABG analysis to obtain the Pao2.
The shunt fraction is the proportion of venous blood that bypasses the alveolar gas exchange surfaces. In normal lungs there is a small amount of shunting of pulmonary arterial blood to the pulmonary veins as a result of:
- Direct arteriovenous communication
- Veins draining into the left ventricle
These are both absolute, or anatomical, shunts, where there is direct communication from pulmonary artery to vein without gas exchange. Shunting may also occur due to:
- Alveoli that have no ventilation or reduced ventilation, resulting in a physiological shunt
The overall severity of shunting is expressed by the shunt equation:
S is the blood flow through the shunt;
T is the overall cardiac output; Cvo2 is the mixed venous oxygen content (i.e. the content of the blood entering the pulmonary arteries); Cao2 is the arterial oxygen content (i.e. the content of the blood leaving the lungs); and Cco2 is the oxygen content at the end of the pulmonary capillaries.
Therefore, if there were no shunt, all of the oxygen from the pulmonary capillaries (Cco2) would get to the arterial circulation (Cao2), giving a difference of zero, and hence no shunt. Cao2 is calculated from the oxygen saturation and haemoglobin concentration measured on arterial blood gas. Likewise, Cvo2 can be calculated from a mixed venous blood gas (such as from a central venous line). Cco2 is much more difficult to estimate, since there is no way of sampling the pulmonary capillaries. It can be estimated from Pao2 (alveolar partial pressure of oxygen, which can be calculated by the alveolar gas equation), but this assumes normal diffusion so only applies in the absence of lung disease.
The shunt fraction is clinically useful in critical care monitoring; abnormalities in the fraction in patients who are intubated and ventilated may reveal underlying problems such as ventilation–perfusion imbalances or atelectasis in the lungs. The normal shunt fraction is less than 5%. Due to the difficulty in reliably calculating the shunt fraction, the diagnosis of a shunt may require confirmation by other investigations. For example, large anatomical shunts, such as from an arteriovenous malformation between pulmonary artery and pulmonary vein, can be visualised by bubble echocardiogram.
1.5 Gas transport in the blood
The transport of gases in the blood is crucial to maintaining a normal metabolic state. O2 is used up by cells in respiration and the product, CO2, then needs to be transported back to the lungs to be breathed out in exchange for more O2. Abnormalities in this process lead to changes in metabolism and acid–base status which can be measured by arterial blood gas analysis (see Chapters 2 and 3).
Arterial blood is normally at 95–98% O2 saturation, i.e. 95–98% of haemoglobin's oxygen-carrying sites are bound to O2). As blood flows through tissues in which the Po2 is lower than in arterial blood, O2 diffuses along its pressure gradient into the tissues. Thus the further from the lungs, the more the O2 saturation falls. Under resting conditions it reaches a low of about 70–90% in total mixed venous blood being returned to the lungs via the heart and pulmonary artery. When this blood is exposed to the higher Po2 in the alveoli, O2 diffuses into it across the alveolar membrane.
O2 constitutes 21% of the atmosphere by volume and atmospheric Po2 is 21 kPa at sea level (Figure 1.9). At an alveolar pressure of 13 kPa, alveolar oxygen diffuses into pulmonary venous blood and raises its O2 content from 15 mL/100 mL to 20 mL/100 mL. Of this amount 19.75 mL is combined with haemoglobin and 0.25 mL is ‘free’ or dissolved in simple solution in the plasma. At this pressure of alveolar O2, haemoglobin in the arterial blood normally becomes 98% saturated with O2 and 2% of the haemoglobin remains unbound, i.e. free of oxygen.
The O2-binding capacity of haemoglobin is influenced by the CO2 content and pH of blood (Figure 1.10). Increased Pco2 causes dissociation of O2 from oxyhaemoglobin because haemoglobin has a higher affinity for CO2 than O2. However, from the alveolar capillaries, CO2 diffuses freely into alveolar air, lowering the CO2 content of the blood and permitting haemoglobin to bind O2 again.
Figure 1.10: Haemoglobin saturation curve. In the normal state, the solid line reflects the affinity of haemoglobin for oxygen. Factors that decrease this affinity cause a ‘right shift’ in the curve, whereas those that increase this affinity (i.e. oxygen is bound more readily) cause a ‘left shift’ in the curve. 2,3-DPG; 2,3-diphosphoglycerate (a by-product of cell metabolism that stabilises deoxyhaemoglobin).
In blood, CO2 is present in both plasma and red blood cells:
- Dissolved in blood plasma (5% of CO2 in arterial blood)
- Bound to haemoglobin as carbaminohaemoglobin within red blood cells (around 10%)
- In the form of bicarbonate attached to a base (85%)
CO2 diffuses readily across the alveolar membrane and into red blood cells. Most CO2 entering red blood cells is rapidly hydrated by the enzyme carbonic anhydrase to form bicarbonate (Figure 1.11).
Figure 1.11: Carbonic anhydrase, the key buffering system of plasma pH homeostasis, bypasses the energetically unfavourable carbonic acid intermediate.
Carbonic anhydrase is one of the fastest-acting enzymes, allowing near-instant equilibration between carbon dioxide and bicarbonate. It is therefore essential in regulating blood and body fluid pH and transporting CO2 out of tissues.
1.6 pH homeostasis
Cells are continually producing acid as a consequence of metabolism. Because most proteins and enzymes require an environment with a pH of 7.35–7.45 in order to function effectively, pH needs to be tightly controlled and the tendency to acidosis countered.
Blood pH is determined by the ratio of plasma bicarbonate to dissolved carbon dioxide in blood ([HCO3–]/[CO2]), which is about 20:1. The normal pH of blood (7.40) is maintained by the gain or loss of H+ or HCO3– via three closely related mechanisms:
- Bicarbonate–carbonic acid buffering system
- Respiratory system buffering
- Renal system buffering
Bicarbonate–carbonic acid buffering system
The bicarbonate–carbonic acid buffering system is the body's first response to changes in blood pH and occurs in the blood plasma:
This reaction is catalysed by carbonic anhydrase. This is an extremely rapidly acting enzyme, so the levels of CO2, HCO3– and H+ are always kept in the same equilibrium.
Compensation When acid or base changes occur, in the plasma they are initially buffered by this equilibrium. However, the bloodstream is not a closed system, and ultimately any excess CO2 and H+ are excreted by the lungs and kidneys, respectively (see below). This is known as compensation.
Plasma bicarbonate Bicarbonate is reported by blood gas analysers. It is usually calculated from the pH and Pco2 because carbonic anhydrase is so efficient that HCO3–, H+ and CO2 can be assumed to always be in equilibrium. Because bicarbonate is freely converted to H+ and CO2, changes in both gas exchange or in the patient's metabolic state affect its concentration.
Respiratory system buffering
This system is the main factor in pH homeostasis: 99% of carbonic acid is excreted from the lungs in the form of CO2, compared with the kidneys’ 1% (see below). The respiratory buffering system is fast-acting, effecting changes in minutes.
When the CO2 pressure rises in the blood it dissociates into HCO3– and H+, lowering the pH. This stimulates the respiratory centre (see Figure 1.12), which acts to increase alveolar ventilation and thus ‘blowing off’ excess CO2, returning the pH to normal.
Renal system buffering
The kidneys help control pH homeostasis by excreting protons (H+) and conserving bicarbonate. This system is slow-acting, taking hours to have an effect.
The base excess is the theoretical amount of strong acid needed to bring a patient's fully oxygenated blood to normal blood pH (pH 7.40) at room temperature and at a fixed Pco2 (5.3 kPa, or 40 mmHg). It is calculated from the serum bicarbonate concentration [(HCO3–)] and pH. Normal base excess is between −2 and +2 mmol/L.
Standard base excess
pH buffering in the blood is augmented by the presence of haemoglobin as an additional buffer to the CO2-bicarbonate system. This means that an abnormal base excess in the blood might underestimate the degree of acid–base disturbance in tissues, which have less effective pH buffering. It is possible to account for this by using the standard base excess, which is reported by most ABG analysers, and is defined as the base excess when haemoglobin is at 50 g/L (5 g/dL). This lower haemoglobin level reflects the lower buffering capacity of tissues outside the blood and is clinically a more useful estimate of extracellular fluid pH in unwell patients.
The anion gap is the difference between the total sodium and potassium ion plasma concentrations and the total chloride and bicarbonate plasma concentrations (in mmol/L):
Anion gap = ([Na+] + [K+]) – ([HCO3–] + [Cl–])
Chloride and bicarbonate are the most abundant anions in plasma. In a patient with metabolic acidosis, a raised anion gap suggests that another anion could have accumulated to cause the acidosis, such as lactate (from lactic acid) or ketones (causing a ketoacidosis). However, if the metabolic acidosis is caused by loss of bicarbonate from the kidneys or gastrointestinal tract, then the anion gap would remain normal. Anion gap therefore provides an indication of how much unmeasured ions are contributing to acidosis, and can help elucidate its cause.
The normal range is 10–18 mmol/L (see ). In acidosis the differential diagnosis is wide, however in general:
- A high anion gap indicates ingestion or production of too much acid, most often from lactic acidosis
- A low/normal anion gap indicates that excessive bicarbonate is being lost by the gastrointestinal tract (e.g. diarrhoea) or due to tubular damage in distal (type 1) or proximal (type 2) renal tubular acidosis
1.7 Neurological control of breathing
Breathing is primarily controlled by the central nervous system (CNS; Figure 1.12). The primary drive to breathe is controlled by sensing of pH at chemoreceptors in the medulla oblongata of the brainstem (central chemoreceptors). Additional chemoreceptors in the aortic and carotid bodies sense O2 and CO2 (peripheral chemoreceptors). Combined, these signals constitute the ‘urge to breathe’ and are known as the respiratory drive.
Respiratory drive: carbon dioxide and oxygen
CO2 is the dominant stimulus to breathing, predominantly through its effects on pH. A brief, complete cessation of breathing causes a gradual rise of Paco2 and a fall in blood pH as CO2 is produced in the tissues, which is rapidly detected by central chemoreceptors.
Figure 1.12: Neurological control of breathing. Respiratory drive is drivent predominantly by pH chemoreceptors. In some situations respiratory centres respond to changes in Paco2, arterial partial pressure of carbon dioxide and Pao2, arterial partial pressure of oxygen.
However, as O2 is consumed from the blood the Pao2 changes relatively little while saturation is on the flat part of the haemoglobin desaturation curve (Figure 1.10), only causing significant changes in Pao2 once the oxygen content has fallen to low levels. CO2 and pH are therefore a more sensitive signal in the control of ventilation by the CNS.
In healthy people at sea level, only 10% of the respiratory drive is due to hypoxic (low O2) stimulation.
Respiratory drive: metabolic acidosis
Metabolic acidosis and alkalosis can also directly affect respiratory drive. Hydrogen ions (H+) stimulate both central receptors in the medulla and peripheral chemoreceptors in the carotid and aortic bodies, increasing respiratory drive. Acidosis (high H+/low blood pH) stimulates respiration; conversely alkalosis depresses it. It is difficult to separate this influence from that of O2 and CO2 because their respective values in the blood are linked.
1.8 Physiological changes during exercise
Patients with newly diagnosed lung disease often initially present with breathlessness on exertion. In order to interpret lung function tests, it is necessary to understand the physiological changes that occur during exercise.
Physical activity is associated with changes in:
- cardiac output
- stroke volume
- heart rate
- systemic and pulmonary blood pressure
- the microcirculation
- regional blood flow
Cardiac output and stroke volume
During the first phase of a period of exercise, there is a sudden initial rise in the cardiac output, followed by a slow increase to the level required by the intensity of the exercise. This level is reached when the O2 consumption is at a steady state.
Physically fit individuals can adjust their cardiac output faster than those who are unfit. During muscular activity for a relatively short effort, their stroke volume rises quickly to a level that remains constant. For a more prolonged effort, their stroke volume will decrease by as much as 16%, but heart rate increases to ensure that the cardiac output remains constant.
During heavy work, heart rate increases until a state of muscular exhaustion is reached. The heart rate achieved at the steady state is determined by O2 demand.
During exercise, systolic blood pressure increases slightly for the initial 1–2 minutes despite the simultaneous dilatation of resistance vessels. Blood pressure subsequently stabilises for each workload at a level specific to the individual. Peripheral resistance falls during muscular activity, as a result of extreme dilatation of the arterioles within muscles, and the pressure in the pulmonary arteries rises along with the cardiac output.
Only a portion of the capillary vascular bed is open at rest. During muscular activity the number of patent capillary vessels and thus the volume of blood flow increases by up to 20 times. Consequently, although the velocity of capillary flow does not change, the diffusion distance that molecules must travel from the blood to the cellular site of metabolic activity is considerably shortened.
The response of the respiratory system during physical activity is to provide adequate O2 through ventilation and diffusion. At rest, the lungs ventilate at a rate of 5–6 L/min. During muscular work, ventilation increases according to metabolic demands; during heavy activity it can reach values 20–25 times the level at rest. Also during muscular work, TLC decreases slightly, VC is reduced and RV rises a little. The pulmonary capillary transit time also decreases with increasing exercise from approximately 0.75 ms to 0.25 ms. This is not a problem in healthy individuals but in those with VQ mismatch, this decrease affects oxygenation during exercise.