VA = k.VCO2 PaCO2 For gas exchange to occur, ventilation must match per- fusion. At the lung apices, ventilat ion exceeds perfusion (V/Q <1), whilst at the lung base, perfusion exceeds venti- lation (V /Q >1). Hence V/Q matching is not perfect. CO2 transportation CO2 is carried by blood: \200 Bound to hemoglobin. \200 Dissolved in the plasma. \200 Dissolved CO2 in equilibr ium with carbonic acid: CO2 + H2O \207\224 H2CO3 \207\224 H+ + HCO3 l \210\222 (Eq.12) A KENDRICK 14 \200 A d[Hb] i.e. anemia dO2 content, so the amount of O2 delivered to the tissues is lower. It does not change the PaO2 and hence there is no change in SaO2. The alveolar gas equation es timates PAO2 in an ideal alveolus and is a guide to alveolar gas exchange: The PaCO2 of normal blood is 4.8 \200\2235.9 kPa. CO2 is in high concentration in the tissu es relative to the blood, so diffuses from the tissues into the blood. The relationship of CO2 content and PaCO2 is linear over the normal physiological range. This relationship allo ws hyperventilation of normal alveoli to compensate for hypoventilation of diseased lung un its. The Haldane Effect describes the shift to the right of the CO2 \200\223Hb curve in the presence of O2. CO2 is displaced from Hb and enters the blood as dissolved gas. l (Eq.14) PIO2 \200\223 PO2 in inspired air; R is VO2 VCO2 and is assumed to be 0.8. PAO2 = PIO2 \200\223 (PaCO2 R) From Eq.14 a number of inferences can be made: \200 For a given PIO2 and R, there is only one PaCO2 for each value of PAO2. A mild reduction in PAO2 can be normalized by iVA, so d PaCO2. Hypoventilation results in an iPACO2 and 6dPAO2 . Maximum PaO2 breathing room air is determined by how low the PaCO2 and hence PACO2 can be reduced to. Normally PaO2 does not exceed 16 kPa. In respiratory failure, PaCO2 may increa se to 12 kPa, if the PaO2 decreases to 4 kPa. Chronically hypoxic patients may manage on a PaO2 of 2.5 kPa. An elevated PaCO2 may occur because of: 1. d VE \200\223 refer to Eq.9 and Eq.10 for chang es in fb and VT; 2. d VA (Eq.11); 3. iVCO2 with no change in VE or VA; 4. V/Q mismatch. A d ecreased PaCO2 indicates an iVA (Eq.11) and the cause of this may be acute (whilst taking t he blood sample) or due to other causes, i.e. hyperventilation syndrome O2 transportation T he binding of O2 to hemoglobin is different to that of CO2. \200 \200 \200 For - PIO2 = 19.7kPa, PaCO2 = 5.33kPa and R = 0.8, the PAO2 = 13.0 kPa. If PaO2 is 13.2kPa, the alveolar \200\223arterial O2 difference (AaDO2) is 0.2kPa. This is within 2kPa and re \202 ects the V/Q mismatch that occurs in normal lungs. The PaO2 of normal blood is 11.3 \200\22313.3 kPa. The O2 \200\223Hb curve is sigmoid shape d and relates O2 saturation (SO2) to PaO2 (Fig. 2.1.4). Gas diffusion Having ventilated and perfused the alveoli, gas exchange of O2 and CO2 across the alveolar capillary membrane must take place. \200 Gas moves from a high pressure to a lower pressure, i.e. O2 moves from the alveoli to the c apillary blood. Gas uptake (V) depends on - pressure difference (P1 \200\223 P2), the prop erties of the gas (D), membrane surface area (A) and membrane thickness (t). Fick \200\231s law of diffusion states: l (Eq.15) D, A and t cannot be measured and are lumped together as TL \200\223 transfer fact or or DL \200\223 diffusing capacity (DL), so Eq.15 becomes. l V = [D x A x (P1 \200\223 P2)] t TL = V (P1 \200\223 P2) (Eq.16) TL is a number of resistances in parallel; Dm \200\223 diffusing membrane capacity , \230 - the reaction rate of CO with hemoglobin and Vc - pulmonary capillary blood vol- u me. These are combined as: l Fig. 2.1.4 Oxyhaemoglobin dissociation curve. V \200\223 mixed venous blood, a \200\223 a rterial blood. The effects of changes in temperature, PCO2, [H+] and 2-3 diphosphoglycerate (DPG) on the af \201 nity of Hb for O2 are shown. 1/TL = 1/Dm + 1/ \230Vc Disease states may reduce gas uptake and TL due to: The upper \202 at portion of the curve (PO2 > 8 kPa) allows for quite large changes in PO 2 with little change in SO2 \200\223 SO2 \211 90%. Within the steeper middle portion of t he curve, small changes in PO2 result in large changes in SO2. It is essen- tial to record the on-air SO2 if studying changes over- night in SO2 using pulse oximetry. Consciousness i s lost when PO2 8 3.5 kPa (SO2 8 50%). The amount of O2 carried is the O2 content and is th e sum of the O2 bound to Hb and of that dissolved in the plasma. l (Eq.17) 1. loss of surface area (dA or dDm - emphysema); 2. imembrane thickness (it or dDm - \201 brosis); 3. d \230 (anemia); 4. dVc (reduced cardiac output). \200 Blood \202 ow through the capillary at rest takes 8 0.75s and equilibrium between pulmona ry venous and alveo- lar gas takes 8 0.25s for PO2 and 8 0.30s for PCO2. At maximal exercis e, blood \202 ow through the capillary takes 8 0.25s, but generally there is little affec t on the equilibration of PO2 and PCO2. O2 and CO2 diffusion are perfusion-limited in norma l lungs, but may be diffusion-limited in diseased lungs. \200 O2 content = (1.39[Hb] x SO2) + (0.023PaO2) (Eq.13) For an [Hb] = 14.6 g.dl \210\2221, SO2 = 98% and PaO2 = 13.33 kPa, the O2 content = 20.18 ml.dl \210\2221. CHAPTER 2.1 Basic physiology 15 The respiratory controller The control of breathing is complex and not fully under- stood. Respiratory control involves both autonomic and volitional elements. In the medulla there are: \200 inspiratory neurons with a pacemaker function, \201 ring at a given rate, but may be modi \201 ed by other factors; neurons that \201 re during (a) inspiration, (b) exhalation o r (c) transition from inhalation to exhalation. Autonomic control The neural structures responsible for the autonomic con- trol are: \200 \200 Hence, the neurons responsible for the autonomic rhyth- mic breathing form the central patt ern generator (CPG), which controls the minute-to-minute breathing in the normal person. located in the medulla oblongata; the dorsal (DRG) and ventrolateral (VRG) respiratory grou ps, each with inspiratory and expiratory neurons. Volitional breathing The system permits: \200 \200 \200 The DRG: \200 breath-holding for periods of time; hyperventilation by ifb and iVT; alteration of the Ti a nd time of exhalation, by dfb and iVT under conscious controlled breathing conditions; chan ges in the breathing pattern in the presence of dis- comfort and anxiety. When experiencing pain or short- ness of breath, ifb and iVE are observed. processes information from the receptors in the lungs, chest wall and chemoreceptors; has a key role in the activation of the diaphragm and the VRG; shows increased neuron activity d uring inhalation; has an important role in (a) determining the rhythm of breathing and (b) regulating the changes in upper airway radius, by stimulating muscles to expand the upper a ir- way during inhalation. \200 Inputs to autonomic controller The brain receives information from a variety of sources (Fi g. 2.1.5): Mechanoreceptors: Activated by distortion of their local environment. Includes r eceptors in: \200 In the pons, the pontine respiratory group (PRG): \200 \200 contributes to switching from inhalation to exhalation; if damaged, there is iinhalation ti me (Ti), dfb and iVT. Upper Airways: sense and monitor \202 ow, probably by temperature change. Inhibit central controller. Nasal receptors Sneeze Diving reflex Epipharyngeal receptors Aspiration reflex Pharyngeal receptors Swallowing Laryngeal receptors Cough Apnoea Slowly adapting receptors Hering \200\223Breuer inflation reflex Hering \200\223Breuer defl ation reflex Bronchodilation Tachycardia Rapidly adapting receptors Cough Hering \200\223Breuer deflation reflex Hyperpnoea Bronchoc onstriction Mucus secretion C-fiber endings Pulmonary chemoreflex Rapid shallow breathing Bronchoconstriction Mucus sec retion Bradycardia Hypotension Fig. 2.1.5 The location of the major upper and lower airway and lung sensory receptors and the primary re \202 exes activated by these receptors. A KENDRICK 16 Ageing and the lungs Ageing causes important changes in the structure and function of the r espiratory system. From birth, the lungs develop and reach their maximum around the age of 18 \200\22325 years. From aged 25 years there is: \200 \200 \200 Pulmonary system, which include stretch receptors in the lungs: \200 Slowly adapting receptors (SARs): located in smooth muscle in the intra- and extrathoracic airways. When stimulated by lung in \202 ation, the expiratory phase of respiration is pro longed. May also be involved in the early termination of inhalation when iVT. Rapidly adapt ing receptors (RARs): located in air- way epithelial cells around the carina and in the lar ge bronchi. Stimulated by chemical (tobacco smoke, his- tamine etc.) and mechanical stimuli . Activation may lead to cough, bronchospasm or increased mucus production. Lung de \202 a tion activates RARs and can contri bute to an ifb and prolonged breaths, i.e. sighs. Hering \200\223Breuer re \202 ex: a re \202 ex that prevents over- in \202 ation of the lungs. Pulmonary stretch receptors respond to excessive stretching of the lung during large inhal ations. When activated, the receptors send action potentials to the pons, inhibiting the in spira- tory neurons, so exhalation occurs. This re \202 ex may only apply in newborn human s. C- \201 bres: believed to be stimulated by chemical (his- tamine, prostaglandins etc.) and mechanical stimuli (ipulmonary capillary pressure). May contribute to changes in fb and VT. Progressive loss of alveolar elastic recoil. Calci \201 cation of the costal cartilages. D ecreased spaces between the spinal vertebrae and a greater degree of spinal curvature. This results in the following gradual changes, which vary from person to person: \200 iCL and dCChest Wall. \200 iFRC, iRV and dVC as TLC remains fairly constant. \200 dPEF and other \202 ow rates. \200 iVD and dVA \200\223 VE and VT unchanged. \200 dVO2 at re st, but iVO2 for a given exercise level. \200 dCardiac output and Cardiac frequency (220 \200\223 age). \200 dPaO2 and dSaO2, but iAaDO2 as PAO2 unchanged. \200 dDm and dA (Eq .15 & Eq.17) and dVC resulting in dTL. \200 Poorer distribution of ventilation. \200 dm aximum inspiratory (MIP) and expiratory (MEP) mouth pressures. dexercise capacity \200\223 however assessed. Chest wall: monitor respiration and alert the controller that the physiology of the ventila tory pump has changed i.e. iRaw or dCRS. Chemoreceptors: located centrally and peripherally , and monitor chemical changes in the blood: \200 When assessing the normal physiology of an individual, it is essential to take into account the age of the subject. Further reading Cloutier MM. Respiratory physiology. Mosby Physiology Monograph Series, 2006. Peripheral chemoreceptors: located in the carotid body and the aortic arch, they monitor ch anges in PaO2, PaCO2 and pH A dPaO2 or a iPaCO2 or a dpH results in a iVE and vise versa. C entral chemoreceptors: located in the medulla and monitor changes in PaCO2 and pH. A iPaCO2 or a dpH results in a iVE and vise versa. The ventilatory response to hypoxia is relativel y \202 at until 8 kPa, after which VE rapidly increases The ventilatory response to hyper capnia is linear, and compared to an awake normal subject the slope of rela- tionship of VE to PaCO2 becomes increasingly \202 atter with the effects of sleep, narcotics and anesth esia. Lung Model 4.2: http://oac.med.jhmi.edu/LungMode l4.2/ Lumb AB. Nunn \200\231s Applied Respiratory Physiology, 6th edn. Oxford: Butterworth-Heinemann, 2005. Schwartzstein RM, Parker MJ. Respiratory Physiology \200\223 A Clinical Approach. Philadelphia: Lippincott Williams & Wilkins, 2006. West JB. Respiratory Physiology: The Essentials, 7th rev. edn. Philadelphia: Lippincott Williams & Wilkins, 2004. Answers If VA = 4800ml.min \210\2221 then PaCO2 = 5.8 kPa and PaO2 = 12.97 kPa. By doubling VD, PaCO2 = 9.3 kPa and PaO2= 8.7 kPa. VT or fb would need to increase to 620ml or 24/min respectively to achieve the original VA This page intentionally left blank G LASZLO 18 2.2 Lung function tests: a guide to interpretation Introduction Breathing tests are used: \200 \200 3. Abnormal control of the rate and depth of breathing leading to inadequate or excessive ventilation. These disturbances can cause breathlessness on exertion or at rest. Breathlessness on exert ion usually occurs in a predictable way; at rest the symptom may be chronic or occur episod ically. In disease states, some correlation is found between the severity of the abnormalit ies of lung function and the amount of breathlessness suffered. In indi- viduals, the impac t of impaired lung function is modi \201 ed by co-morbidity, general health and current ps ychological state as well as personality, level of habitual exercise and expectations. To look for evidence of respiratory impairment. If present, to measure lung function using tests which are sensitive to changes in the severity of the patient \200\231s condition. Cl inicians may look for diagnostic patterns of impairment as part of the investigation of sym ptoms, especially breath- lessness; these are most informative when the CXR shows no locali zing disorder. Epidemiologists use them to study the effects of disease and the environment on the lung. This section describes the investigation of conscious, coop- erative adults w ho can perform the required voluntary breathing maneuvers. Reference values are available f or most populations; numerical results may be interpreted using population means and upper and lower 90% con \201 - dence intervals. Good technique is essential. The three main type s of lung function disturbance are: \200 Spirometric tests of expiratory and inspiratory \202 ow and volume Spirometry is simple a nd inexpensive. Its interpretation depends on an understanding of static lung volumes. VC: vital capacity is the volume of air that can be delivered by a full expiration from total l ung capacity to residual vol- ume or inspiration by the reverse procedure. This may be redu ced because of 1. Air \202 ow obstruction which can cause airway closure at Ventilatory impairment: mechanical damage to the lungs or chest wall that make the breathin g more dif \201 cult). Damage to the gas exchanging surface: a reduction of the number of pulmonary capillaries in contact with healthy alveoli. Abnormalities of blood gasses: these are caused by 1. Lung failure (damage to the gas exchanging mechanism). 2. Pump failure (w eakness, fatigue or paralysis of the the end of expiration. RV is increased. 2. Restriction to inspiration caused by reduced volume of the alveolar gas, by abnormalitie s of the chest wall or by weakness of the respiratory muscles. Total lung capacity TLC is r educed. respiratory muscles). Out Out FVC 6 6 r i a d e r i p x e r i a d e r i p x e 5 5 4 4 Restrictive ) s e r t i l ( ) s e r t i l ( FEV1 3 3 f f o e m u o V o e m u o V 2 2 Obstructive 1 1 l l In In 0 1 3 2 Time (seconds) 4 5 6 1 3 2 Time (seconds) 4 5 6 0 Out Out After 6 weeks of corticosteroids 6 6 r i a d e r i p x e r i a d e r i p x e First attempt Third attempt Second attempt First attempt Third attempt Second attempt After salbutamol 5 5 a 4 b 4 ) s e r t i l ( ) s e r t i l ( 3 3 f f Before salbutamol o e m u o V o e m u o V 2 2 1 1 l l In In 0 1 3 2 Time (seconds) 4 5 6 0 5 6 1 3 2 Time (seconds) 4 Fig. 2.2.1. Volume \200\223time curves obtained during forced expiration using a wedge-bell ows spirometer. (a) The subject has taken a full breath in and exhaled forcibly and fully. Maximal \202 ow decelerates as forced expiration proceeds, because the airways decrease i n size as the lung volume diminishes. Exhalation is termina ted when the expired \202 ow rate falls to <0.25 litres/sec (as here) or at 14 sec, whichever is sooner. (b) Obstructive and restrictive patterns. In obstruction, FEV1/FVC is low; in restrictive disorders it is normal or high. (c) Straight line traces (a) in central airways obstruction, \202 ow is c onstant through the \201 rst half of expiration; (b) Tracheo-bronchial collapse occurs in severe emphysema and tracheomalacia the \201 rst 200 ml is exhaled rapidly after which t he compressed airway behaves like a \201 xed central obstruction. (d) Response of FEV1 to treatment. A patient with moderate asthma tested before and after salbutamol and after a c ourse of prednisolone. FEV1 improves more than FVC. CHAPTER 2.2 Lung function tests: a guide to interpretation 19 obstruction, i.e. narrowing of the caliber of the airways. This is exaggerated by the effor t of forced expiration; exhalation is impeded and therefore \202 ow rate during expiratio n is reduced. COPD (chronic obstructive pul- monary disease) is de \201 ned as an irrevers ible reduction of FEV1/FVC to below 70%. PEF: peak expiratory \202 ow rate is the maximum \202 ow at the start of a short forced exhalation. (Peak \202 ow meters measure the \201 rst 10 milliseconds. The results from these are similar to the \201 rst part of an e xpiratory \202 ow-volume loop.) PEF is reduced if there is narrowing of either proximal o r distal airways or both, so it is very useful for identifying variability when spirometry indicates the presence of air \202 ow obstruction. When a diagnosis of asthma has been mad e, PEF is used to assess daily and hourly variation. PEF is deceptively simple and has to b e interpreted cautiously because: 1. Weakness or sub-maximal effort will produce low results. 2. Very low readings are obtain ed when there is obstruc- tion of the larynx or trachea. Fig. 2.2.2 Maximal expiratory and inspiratory \202 ow \200\223volume loops (1) Normal. Th e subject has taken a full breath in and exhaled forcibly and fully. Maximal \202 ow dece lerates as forced expiration proceeds, because the airways decrease in size as the lung vol ume diminishes. Maximal \202 ow rates are much greater than \202 ow rates during quiet breathing (3b). MIF is approximately the same as MEF but is sustained throughout mid-inspir ation because there is no impediment to the opening of the airways when negative pressure i s applied to the outside of the lung. (2) Mild air \202 ow obstruction showing reduction o f \202 ow rate at mid-expiration and near RV. MIF = MEF. (3a) Severe air \202 ow obstruc tion demonstrating airways collapse shortly after the beginning of forced expiration. MIF = MEF. (3b) Tidal breathing without forcing may achieve higher \202 ow rates than forced e xpiration, which may cause the airways to collapse. (4) Obstruction of a central airway (gl ottis, larynx or trachea). In this example, MIF < MEF, indicating that the obstruction is i n a collapsible airway outside the thorax. If the obstruction is \201 xed, MIF = MEF. 3. PEF does not re \202 ect accurately the severity of COPD. Flow volume loops Graphic displays of maximal expiratory and inspiratory \202 ow during forced expiration a nd inspiration between TLC and RV plotted against lung volume (see Fig. 2.2.2). During forc ed expiration \202 ow is characteristically greatest at TLC, because the lung is at its m ost elastic, the airways are wide open and the respiratory muscles are at their greatest le ngth and ef \201 - ciency ( \200\230peak \202 ow \200\231). In normal subjects \202 ow decelerates steadily towards RV when the lung is empty and no further \202 ow occurs. Th is is because the airways progressively nar- row and may collapse one by one because of the pressure around them. In COPD, particularly emphysema, airway collapse occurs at relativel y high lung volumes. Tracheal or laryngeal obstruction is characterized by a very low peak flow and a constant flow rate throughout expiration. Forced inspiration opens the airways m aximally so the inspiratory loop shows a more or less constant flow. Maximum inspiratory \202 ow is usually the same as PEF in normal subjects, greater in COPD and less in some cas es of central or upper airway obstruction. FVC: forced vital capacity is the volume of air that can be delivered by a forced expiratio n from total lung capacity to residual volume (RV). FEV1 (the volume expired from full insp iration in the initial sec of a forced expiration from full inspiration) should be greater than about 75% of FVC (according to age). Reduction of the ratio of FEV1/FVC points towards air \202 ow Fig. 2.2.3a Subdivisions of total lung capacity \200\223 measurement of static lung volume s by closed-circuit helium dilution. The patient rebreathes quietly from a spirometer of kn own volume initially containing about 10% helium, 21% oxygen and nitrogen. Oxygen is added as it is consumed and carbon dioxide removed to maintain a constant volume of gas. The test ends when the helium concentration ceases to fall. FRC is calculated using an equation whi ch depends on the fact that the amount of helium is constant though its concentration falls as it diffuses into the lungs. [ ] denote concentrations. [Initial helium] x initial spiro meter volume = (Initial spirometer volume + FRC) x [ \201 nal helium]. In this example (em physema) FRC = 6(10 5)/5 = 6 litres. Residual volume (RV) is derived by measuring a full ex piration from FRC. After this a full inspiration yields the inspired vital capacity (IVC) a nd thence total lung capacity (TLC). In patients with air \202 ow obstruction IVC is usual ly greater than FVC and relaxed expired VC. In this example IVC = 4.25, EVC 3.5, TLC = 9, t he best estimate of RV = 4.75 litres. For abbreviations see text and Fig. 2.2.3a. G LASZLO 20 8 TLC TLC 7 6 ) s e r t i l ( 5 TLC FRC s g n u TLC Tidal volume 4 l FRC RV n FRC i r i a 3 f o e m u o V RV FRC RV 2 l RV 1 0 Normal Fibrosing alveolitis (restrictive) Low FRC, RV & TLC Tidal volume often low Airflow obstruction and lung fibrosis (mixed) COPD (obstructive) High or normal TLC High RV and FRC Tidal volume varies among patients Fig. 2.2.3b Static lung volumes in obstructive and restrictive disorders. there is lung \201 brosis. Removal of lung tissue leaving nor- mal lung in place causes o nly a slight fall of TLC because the healthy lung can expand to compensate. ERV: expiratory reserve volume is the difference between FRC and RV. It is reduced in obesity; obese subje cts breathe at low lung volumes and this accounts for the ease with which they develop low arterial oxygen levels if the breath is held IC: inspiratory capacity is the volume that ca n be inhaled from FRC to TLC. It can be measured using a portable spirometer and is used to identify dynamic hyperin- \202 ation. The test is helpful because TLC usually does not v ary very much in individual cases of asthma and COPD, while any situation which increases t he rate of breathing tends to cause the resting lung volume to increase. Static lung volumes The volume of air in the lungs can be measured by: \200 Insoluble gas analysis, e.g. helium dilution. The subject is connected to a closed circuit of known volume contain- ing helium. Oxygen is supplied and carbon dioxide absorbed. The he lium concentration falls by an amount which re \202 ects the volume of the lung. A similar test involves plotting the change of expired nitrogen concen- tration when an oxygen-rich mixture is inhaled. Body plethysmography. The subject sits in a closed booth ( \200\230body box \200\231, plethysmograph) of known volume and breathes in and out against a closed tub e for a few sec- onds. According to Boyle \200\231s Law the ratio of the pres- sures in the mouth and around the subject is determined by the ratio of the volumes of the lungs and th e box. Both these methods measure functional residual capacity (FRC): the volume of air at the end of a quiet expiration. \200 Ways of assessing changes in air \202 ow obstruction with- out maximal effort \200 FRC is reduced when the elasticity of the lungs is increased, e.g. in lung \201 brosis; i t is increased when the elastic recoil is reduced, as in emphysema. In health, the respirat ory muscles are inactive at FRC. In airflow obstruction the need to take another breath may be felt while the patient is still exhaling. This phenomenon is known as dynamic hyperin \202 ation and occurs mainly in exercise and during exacerbations of asthma and in COPD. Dy namic hyperin \202 ation is important because the work of breathing and the sensation of r espiratory effort increase markedly at high lung volumes RV: residual volume is the volume of air in the lungs after a full expiration. As stated before, it is increased when the lun gs fail to empty because of airway obstruction. It is reduced when the lung volumes are sma ll; a fall of RV with- out any other abnormality may occur early in the course of interstit ial pulmonary \201 brosis or granulomatous disease. TLC: total lung capacity is the volum e of air in the lungs at full inspiration. Inspiration is maximal when the lungs are at ful l stretch. It follows that TLC is increased when lung elasticity is lost, as in emphysema, and reduced when Total airways resistance can be determined by measuring the \202 ow at the lips during qu iet breathing and estimating the pressure difference between the pleura and the mouth. Resi stance is normally low and it requires little physical effort to achieve the relatively low \202 ow rates required during tidal breathing; greater pressure differences are required if all or some of the airways are narrowed. Resistance can be measured directly with the s ubject breathing normally while seated in a closed body plethys- mograph. The higher the re sistance to the \202 ow of air in the airways, the greater is the pressure swing in the b ox because the \202 ow of air in and out of the lungs is impeded. Flow at the mouth is me asured at the same time; resist- ance can be calculated as pressure swing/ \202 ow rate. R esistance and impedance of the lung can be estimated during quiet breathing by a commercial device which generates pressure waves at the mouth using a loud- speaker. The \202 ow wa ves that result depend on the resist- ance to \202 ow and the elasticity of the lungs and airways. The test is easy to apply and repeatable and the concept CHAPTER 2.2 Lung function tests: a guide to interpretation 21 is quite simple but the assumptions and calculations are complex and the results are not di rectly comparable to other measurements. The patient inhales from full expiration from a reservoir containing a trace of CO (0.03%), about 10% helium (or other non-absorbed gas) and 16 \200\22320% oxygen. Helium dilution is used to measure the accessible volume of alveolar gas (VA). Carbon monoxide is both dilute d and absorbed, thus: inspired[CO]/expired[CO] is greater than inspired[He]/ expired[He]; i .e. the ratio of CO uptake to helium dilution (CO ratio) >1. It is assumed that CO is absor bed exponen- tially during the period of breath-holding; because Pco is zero in the pulmona ry blood the pressure gradient is the alveolar pressure of the gas. Therefore: DLco = VA x loge(CO ratio) x (1/breath-holding time) x (1/dry barometric pressure). The units are CO up take per unit time per pressure unit difference from alveolar gas to blood, corrected to 0 deg C and dry. DLco/VA is calculated by dividing DLco by VA measured at body temperature an d pressure, saturated with water vapor. The amount of CO extracted depends on: The diffusin g capacity of the alveolar membrane, comprising: \200 The area of the gas exchanging surf ace of the lung. \200 The thickness of the alveolar capillary barrier. Response to bronchodilators and bronchoconstrictors The response of FEV1 and other measures of airflow obstruction to bronchodilators is measured routinely, without any consensus as to how this should be performed or interpreted. It is mainly used to identify untreated ast hma, when dramatic improvements of 0.5 litres or more may be seen after only 200 mcg of inh aled salbutamol. Disappointingly there is no test which identi \201 es asthma in the prese nce of COPD. An improvement of 15% or 0.4 litres (the greater) after 2.5 mg nebulised salbu tamol points towards some potential for reversibility, but current guide- lines emphasize t he need for several days of therapy rather than a single laboratory test to assess this pot ential. In COPD, post-bronchodilator FEV1 and VC vary less than pre-bronchodilator readings and should ideally be used to measure changes of lung function over time in longitudinal s tudies of obstructive disorders. Bronchial challenges with histamine, methacholine, cold ai r or intensive exercise are used to con \201 rm asthma in individuals with normal resting spirometric tests. Asthmatic subjects react to pharmacological bronchoconstrictors with a 2 0% fall of FEV1 at a much lower dose than non-reactive individuals. The pulmonary capillary blood volume (the volume of hemoglobin in contact with the inhaled gas). DLco depends mainly on alveolar function except: \200 Diffusing capacity (synonym transfer factor) of the lung for carbon monoxide (DLco) Carbon monoxide (CO) combines avidly with haemo- globin. The uptake of a trace of CO can therefore be used to measure the capacity of the whole lung to transfer CO from inspired air to hemo globin and thus assess the integrity of the gas-exchanging function of the whole lung. In p ractice the single breath breath-holding test is commonly used and normal values are availa ble for many populations (see Fig. 2.2.4). When the airways are abnormal and a deep breath is not evenly distributed to all parts of t he lung. When the concentration of hemoglobin in the red cells is not normal. There are two ways of reporting diffusing capacity. DLco is the rate of uptake of CO per un it of alveolar Pco in the whole lung. In some situations it can be helpful to divide this b y the lung volume; this yields an index known as diffusion Fig. 2.2.4 Measurement of CO diffusing capacity by the single breath breath-holding method. G LASZLO 22 or transfer coef \201 cient DL/VA. In practice both are useful in separate situations. The calculation of DLco assumes that regional variations of ventilation, perfusion and diffusi on are averaged out. In patients with respiratory failure severe ventilation \200\223 perfu sion mismatching can result in marked abnormalities of CO2 and O2 exchange when DLco is nor mal. Conversely, a low DLco is compatible with a normal resting arterial Po2. Oxygen exchan ge in exercise is invariably abnormal when DLco is low. Interpretation of DLco DLco and DL/ VA are useful clinically in a number of situations. \200 When VC, FEV1, FVC and [Hb] are all normal, a low DLco strongly suggests disease involving the alveoli. In air \202 ow obs truction a low DLco and DLco/VA suggest alveolar destruction (emphysema). In contrast, they are sometimes abnormally high in asthma. In restrictive pleural and chest wall disease, a high DLco/ VA suggests that there is no underlying lung disease. When there are widespread radiological lung shadows, such as in sarcoidosis or some occupational lung dis- eases, DLc o re \202 ects lung impairment and disability but is not correlated directly with the exte nt of the abnor- mality on the plain CXR. Polycythaemia, pulmonary plethora such as in heat fail- ure or left-to-right shunting and pulmonary haemorrh- age cause an increase in DLco because of increases in the volume of hemoglobin in contact with the inspired air. breath for the full 14 sec. Forcing expiration causes more airway closure and true residual volume is easier to each with a relaxed expiration. In normal subjects FVC is the same as VC or better according to the equipment used. When both are measured, FEV1/vital capacity i s the taken to be the lower of the estimates. However, most COPD guidelines have employed F EV1/FVC for simplicity. In most healthy subjects this ratio is greater than 70%. 14 sec for ced expirations are uncomfortable. 6-sec readings of FVC, yielding FEV1/FEV6, are receiving increasing attention; the lower limit of normal being 73%. Why are DL/VA (diffusion or tra nsfer coef \201 cient) and DLco both used? As shown in the calculation, diffusing capacity is the prod- uct of the diffusion coef \201 cient (uptake per liter of lung vol- ume) and the lung volume at which the measurement was made. In normal subjects the pulmonary capill ary blood is distributed to the alveoli which are ventilated; as a result the diffusion coe f \201 cient is much higher than in full inspira- tion. As the lung volume is increased th e coef \201 cient falls but proportionally less than the rise of lung volume. Therefore, o verall, diffusing capacity is higher near TLC. When TLC is high, as in pulmonary emphysema, DL/VA is found to be more sensitive to changes in pulmonary vascu- larity than DLco. In re strictive alveolar diseases such as advanced pulmonary \201 brosis, diffusing capacity is low but the coef \201 cient DL/VA is usually within or near normal limits. If it were not , the gas exchanging capacity might be insuf \201 - cient to sustain life. When restrictio n to inspiration is caused by pleural or chest wall disease, without lung dis- ease, transf er coef \201 cient is high as it is in normal subjects who have taken an incomplete inspir ation; this can be used to help determine whether there is underlying lung disease. Practice points: frequently asked questions What are reference (normal) values? Lung volume s and diffusing capacity are dependent on height, age, sex, and sometimes in \202 uenced b y body mass. There are substantial published racial differences. The most striking of these is the relatively lower lung volumes seen in those of black African descent; their higher diffusing capac- ity and coef \201 cient result in an overall advantage in athletics. A re ading of 1.64 standardized residual deviations from the predicted population mean can be in terpreted as abnor- mal in that only 5% of a healthy population will be below this reading; greater deviations obviously can be inter- preted with greater con \201 dence. The use of \200\230% predicted \200\231 is helpful in giving a feel for the size and shape of the lu ngs and in tables describing the abnormalities found among groups of patients with speci \201 c disorders. The common assumption that 80% usually de \201 nes the lower limit of no r- mal is highly misleading and often leads to over-reporting of abnormalities. COPD guidel ines use FEV1/FVC rather than FEV1/VC; does this matter? Physiologists prefer FEV1/VC becau se it is a better diag- nostic tool. In obstructive diseases, FVC almost always underestima tes VC even if care is taken to continue the Further reading Hughes JMB, Pride NB. (eds). Lung Function Tests: Physiological Principles and Clinical Applications. London: Saunders, 1999. MacIntyre N, Crapo RO, Viegi G, et al. Standardization of the single- breath determination of carbon monoxide uptake in the lung. Eur Resp J 2005; 26: 720 \200\223735. Miller MR, Crapo RO, Hankinson J, et al. General considerations for lung function testing. Eur Resp J 2005; 26: 153 \200\223161. Miller MR, Hankinson J, Brusaco V, et al. Standardization of spirometry. Eur Resp J 2005; 26: 319 \200\223338. Pellegrino R, Viegi G, Brusaco V, et al. Interpretative strategies for lung function tests. Eur Resp J 2005; 26: 948 \200\223968. Wanger J, Clausen JL, Coates A, et al. Standardization of the measurement of lung volumes. Eur Resp J 2005; 26: 511 \200\223522. Vital capacity (VC) VC low VC normal FEV1/VC not low FEV1/VC low FEV1/VC normal FEV1/VC low TLC not low TLCO low TLC not low TLC low TLC low Dyspnoea appropriate to FEV Yes No Basal crackles Basal crackles Airflow obstruction Mixed Restrictive ventilatory defect Yes C H A P T E R No Yes Yes No No ? Evidence of pulmonary vascular disease Spontaneous variation or response of PEF and FEV1 >15% after bronchodilators P1 max normal P max low 2 ? Fibrosis, alveolitis, heart failure or chronic infection . Assess options 2 Yes L u n g No Yes No 1 2 3 Lung/thoracic disease Neuromuscular disease 15% variation in PEF or FEV1 over 24 h period, after vigorous exercise at 80% maximal or af ter specific challenge f u n c t i o n ? Evidence of pulmonary vascular disease: ECG, pulmonary artery pressure, mismatched perfus ion defect, abnormal dead space Pulmonary vascular disease Yes No Yes Irreversible airflow obstruction Asthma Mixed ? All options 1-3 assessed? No No t e s t s : a Chronic bronchitis Unexplained dyspnoea No Yes Yes ? PEF (litres/min) < FEV. (litres) x 100 Low PCO2, irregular breathing, frequent sighs, background of anxiety or bereavement Pulmonary vascular disease considered Yes g u d e Improvement afterr steroids No Yes i 2 No Yes Sputum > 5 ml P1 max low? No No Yes t o No ? Yes 50% chance of central airway obstruction 1 i No n t e r p r e t a t i o n 2 1 Central airway obstruction Diffuse airways obstruction Major component of emphysema Look for evidence of thyroid or heart disease, with or without lung disease Look for evidence of neuromuscular disease, with or without lung disease Psychogenic dyspnoea with or without lung disease Low TLCO/VA \200\231 Obliterative bronchiolitis Flow at 50% VC PEF No Yes Yes Fig. 2.2.5 2 3 P PALANGE 24 2.3 Exercise testing The ability to exercise largely depends on the ef \201 ciency of the integrated physiologi c responses of the cardiovascular and respiratory systems to couple the metabolic needs of contracting skeletal muscles. In healthy subjects, exercise tolerance is largely in \202 u enced by age, gender, level of day life activity and \201 tness. In patients with heart o r lung diseases, exercise tolerance is limited by symptoms (e.g. dyspnoea, leg fatigue) cau sed by abnormal cardiovascular, ventilatory and metabolic responses to exercise load. The c auses of exercise intolerance can classified as \200\230central \200\231 (e.g. ventilatory limitation, circulatory limitation) and \200\230peripheral \200\231 (e.g. muscle dysfunct ion). In patients with chronic pulmonary or heart diseases, central and periph- eral abnorm alities often co-exist.