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Home , Airway resistance

ADJUNCTIVE MEDICAL KNOWLEDGE

Pulmonary Physiology, Pathology, and Ventilation- Studies

Roger H. Secker-Walker

St. Louis University School of Medicine, St. Louis, Missouri J NuciMed19: 961—968,1978

Much of our present understanding of regional and allow collateral ventilation to take place. The function derives from experiments using radio canals of Lambert, which extend from respiratory active tracers. Today studies of regional pulmonary bronchioles to neighboring alveolar ducts and sacs, blood flow and regional ventilation are readily avail may serve a similar function (5). able in most nuclear medicine laboratories. The mucosa of the bronchial tree is lined by a This review serves to emphasize the relationships ciliated columnar epithelium as far as the terminal between lung structure, function, and pathophysi bronchioles. A few goblet cells are found in the ology and to relate these to the procedures that are larger airways. Bronchial glands lie beneath the mu currently performed in nuclear medicine. cosa. Clara cells are found protruding through the cilia in increasing numbers as the terminal airways AIRWAYS AND ALVEOLI are approached. The alveoli are lined by Alveolar The airways divide about 16 times, in an irregular Type I cells, with Alveolar Type II cells, or granular dictotomous fashion, before the terminal bronchioles pneumocytes, occupying the corners, while the al are reached. Beyond this level, the respiratory bron veolar macrophages creep about the surface of the chioles divide two to seven times to reach alveolar alveoli, removing inhaled debris. A thin film of ducts, alveolar sacs, and alveoli. Although the walls surfactant, produced by the Alveolar Type II cells, of the bronchi contain cartilaginous plaques, much spreads as far as the entrance of the terminal bron of their support, and all that of the bronchioles, chioles. It may well be continued up the peripheral comes from the meshwork of surrounding alveoli airways, perhaps produced by Clara cells, to mingle extending through the lobules, segments, and lobes with the mucous blanket that starts at the terminal to the pleural surface. Smooth muscle and connective bronchioles and moves continuously towards the tissue encircle the bronchial tree from the larynx to larynx at an ever-increasing velocity (6). the alveolar ducts. It is important to realize that the cross-sectional area of the bronchial tree increases BLOOD VESSELS AND LYMPHATICS very rapidly beyond the terminal bronchioles, and The pulmonary arterial branches follow the divi that airflow rates, differences, and airway sions of the bronchial tree. The pulmonary arterioles resistance are very low here during normal breath that accompany the terminal bronchioles are about ing (1—3). 100 @L@fldiameter, while the precapillary vessels are The alveoli are packed together like the cells of about 35 ,@in diameter and number 250—300mil a honeycomb. They are surrounded by a three lion, each vessel serving one alveolus. Anastomoses dimensional network of collagen and elastic fibers, between the pulmonary capillaries and bronchial which is continuous with that of the airways and capillaries may be found along the respiratory bron blood vessels and extends to the visceral pleura. The chioles. Each alveolus is surrounded by about 1,000 structural arrangement ensures considerable stabil capillaries in a richly interlacing pattern (3) . The ity, because changes in one alveolus—for instance, shrinkage—will be mitigated by opposite changes in Received Nov. 28, 1977; revision accepted March 1, 1978. surrounding alveoli (4). For reprints contact: Director, Division of Pulmonary The communications between alveoli (pores of Diseases, Dept. of Internal Medicine, St. Louis University School of Medicine, 1325 South Grand Blvd., St. Louis, MO Kohn) become more numerous in older subjects, 63104.

Volume 19, Number 8 961 SECKER-WALKER

@ capillaries are 7—10 in diameter with endothe weight is greatest. This means that in healthy hum that seems to have quite tight junctions. The the alveoli at the top of the lung are more expanded pulmonary veins drain blood from the alveolar capil than those at the bottom, and hence less compliant. laries, as well as the peripheral parts of the airways Thus during normal tidal more air will and the pleura. They lead towards the hilum sepa enter the lower part of the lung because this region rately from the bronchial tree at the periphery of is more compliant and expands more for a given lobules, to empty into the left atrium. change in pressure than the upper part (7—10). The bronchial arteries usually arise from the aorta, This effect of gravity, or acceleration, is seen in and accompany the airways, nourishing them as well any position. The more dependent parts of the lung as the pulmonary arteries and veins. Small bronchial exchange more air for a given change in pleural pres veins drain into the right atrium. Anastomoses with sure than the less dependent parts. However, the pulmonary capillaries exist as indicated above, and support of the lungs within the chest, the shape of the most of the venous return from the bronchial circu thorax, variations in local pleural pressure over ribs lation is through the pulmonary veins. or interspaces, and the use of intercostal muscles or The pleura is richly supplied with lymphatic yes the diaphragm may all influence the distribution of sels. Within the lung parenchyma, lymph vessels start a breath within the lungs and so modify the effect in the interstitial spaces and gather around broncho of gravity or posture. vascular bundles. Their endothelium has large fenes Any disease process that alters trations, and they are equipped with valves, directing on a regional basis will alter the local compliance. lymph flow towards the hilar lymph nodes. Lym For instance, inflammatory, edematous or fibrotic phatics are not found around alveoli. disease processes are all associated with decreased compliance, largely because the inflammatory exu MECHANICS OF BREATHING date, edema fluid, or collagen tissue infiltrate the During normal tidal breathing, the volume of air lung parenchyma or fill the alveoli and require a in the lungs at the end of each expiration—called greater force to overcome them than healthy lung functional residual capacity—is determined by the tissue. Such regions will shrink in volume, and also balance between the forces of the lung receive less air than surrounding normal lung during and the elastic recoil forces of the chest wall. The each breath. Destruction of lung parenchyma by recoil forces in the lung are due in part to the struc emphysema is associated with an increase in static tural arrangement of the alveoli, with the collagen compliance because the structural basis for elastic and elastic fibers intertwined within their walls, and recoil and surfactant are lost. in part to the surface tension generated by surfactant. The compliance of the chest wall can also be al The surface tension increases as the lungs get larger, tered by conditions such as obesity and kyphoscolio and so do the forces developed by the structural sis, in which it is reduced, or muscular paralysis, in arrangement of alveoli and connective tissue. Thus, which it is increased. as the lungs expand, greater are required The airways offer resistance to airflow—resistance to draw in more air, and likewise a greater force is being an expression of the ratio of the driving pres available to expel air. sure to the airflow rate. It has been shown that about Compliance of the lungs depends not only on their half of the total airway resistance lies above the structural integrity but also on the degree of expan larynx. Within the bronchial tree, however, most Sion. For instance, as total lung capacity is ap airway resistance lies in the larger airways. Only proached, the lungs become less compliant (that is, 10—20%is accounted for by the vast majority of they are stiffer) than they are at functional residual small airways (arbitrarily referred to as those less capacity. The is typically less than 2 mm in diameter) (11). In the larger airways, than atmospheric (about 5 cm H20 less at functional air flow is turbulent and the pressures required to residual capacity), because the recoil forces in the generate flow are influenced by the square of the lung tend to collapse the lung, pulling inwards velocity of the gas and by its density. In the smaller against the parietal pleura. The weight of the lung airways where air flow is thought to be laminar, within the thorax causes this pressure (negative with Poiseuille's Law holds good: resistance to flow is respect to the atmosphere) to be unevenly distrib directly proportional to the length of the tube and uted from top to bottom of the lung. Intrapleural inversely to the fourth power of the radius. In such pressure is most negative (about —10 cm H20) at small airways, gas density plays no part in resistance the top of the lung, where the weight of the lung has to airflow. Gas influences both turbulent very little influence, and least negative (about —2.5 and , but its effect on turbulent flow is cm H20) at the bottom, where the effect of the very small.

962 THE JOURNAL OF NUCLEAR MEDICINE ADJUNCTWE MEDICAL KNOWLEDGE

During inspiration the airways expand and airway systemic circulation. Even in states of high cardiac resistance diminishes. During expiration they narrow output—such as during exertion—the pulmonary ar and, towards residual volume, airway resistance in terial pressure rises very little; vascular resistance creases several-fold. As air-flow rates increase, flow actually decreases. becomes more turbulent and airway resistance in Gravity, acceleration, and posture play important creases (12). parts in the distribution of blood flow within the Expiration during a tidal breath is a passive proc lungs. As with ventilation, the support of the lungs ess, the energy coming from the elastic recoil forces within the chest, and the shape of the thorax, may within the lungs. During a forced expiration, pleural modify the effect. pressure is increased. The driving force in the alveoli The low pulmonary arterial pressure is barely suffi is the sum of both pleural pressure and elastic recoil dent to raise blood to the apices of the lungs in the pressure. However, the pleural pressure is trans upright position, so that very little blood flows there. mitted to the airways and will compress them at that In this region of the lungs, alveolar pressure exceeds point along the airways where pleural pressure just pulmonary arterial pressure and the capillaries are exceeds the pressure within the airway. This so virtually closed. Once pulmonary arterial pressure called “dynamiccompression of the airways― limits exceeds alveolar pressure, blood flow increases and the maximum air-flow rates that can be generated the flow rate then depends on the difference between during a forced expiration. The force causing the these two pressures. Pulmonary venous pressure cx air to leave the lungs, once dynamic compression ceeds alveolar pressure farther down in the lung, occurs, is elastic recoil. Because elastic recoil gets and at this point the driving force for blood flow is less as lung volume diminishes, so air-flow rates the difference between pulmonary arterial pressure lessen as lung volume diminishes. and pulmonary venous pressure. Both increase to Airway resistance is increased in any condition gether relative to alveolar pressure so that capillaries associated with narrowing of the airways, such as are more dilated, offering less resistance, and flow bronchospasm, edema of the bronchial walls, excess increases further (14). At the bases of the lungs, , or tumors, strictures, or foreign bodies. In interstitial pressure is thought to compress the extra addition, any process that weakens the support of the alveolar vessels, reducing blood flow. The vertical airways within the lung and allows them to become gradient of blood flow is least at residual volume and distorted, such as emphysema, will be associated greatest at total lung capacity. In addition, vascular with increased airway resistance. A further mecha resistance increases at the extremes of the lung vol nism for reduced air-flow rates in emphysema is the ume. As residual volume is approached the extra loss of elastic recoil, the main driving force for ex alveolar vessels are compressed, while towards total piration. lung capacity the capillaries are stretched thin. Al The amount of air entering any given region of though the intraluminal pressures are different, the the lung will be related to both local compliance and lung parenchyma offers support to the blood vessels local airway resistance. The product of these two just as it does to the airways (10,15—17). called the time constant—gives an indication of the time required for proper expansion of the lungs; this VENTILATION-PERFUSION RATIOS will be shorter in lungs with low compliance and In the upright position, breathing at functional longer in those with high compliance, or high airway residual capacity, ventilation per unit volume in resistance, or both. This also applies on a regional creases one and a half to twofold between the upper basis, so that some parts of a lung may require more zones and the lower zones, while blood flow in time than others to fill or empty properly. If the time creases three- to fivefold (18). for a breath is shorter than this, ventilation becomes The different gradients in ventilation and blood more uneven and the lungs begin to behave as if they flow down the normal upright lung mean that the were stiffer. Such lungs show frequency dependence ratio in which ventilation and blood flow mix is not of dynamic compliance : that is, as the respiratory uniform. In fact the ratio changes from about 2 or rate increases, dynamic compliance decreases (13). 3 in the apices to about 0.6 in the bases. It has been calculated that at the apices the P02 and PCO2 are BLOOD FLOW 132 and 28 mm Hg, respectively, while at the bases The lungs are remarkable because the full cardiac the figures are 89 and 42 mm Hg. In spite of this, output passes through them at such a low driving the overall performance of the lungs leads to a fall pressure—the mean pulmonary artery pressure being of only 4 mm Hg in the P02 between alveolar P02 11 mm Hg. Pulmonary vascular resistance (the ra and arterial P02, the PA-a02 gradient, is a con tio of pressure to flow) is much less than that in the venient measure of how closely ventilation and per

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fusion are matched. The worse the match, the greater Two rather different methods of studying regional the difference, indicating the presence of disease. ventilation are in vogue. In the quasi-static method, Determination of the ratio of physiologic dead radioactive xenon is inhaled to total lung capacity space to , (VD/VT) calculated from the and its distribution measured during breath holding. modified Bohr equation The gas is then rebreathed, through a closed circuit with a CO2 absorber, until equilibrium is reached, r PaCO2—PECO21 at which time its distribution is again measured dur @ PaCO2 @J' ing a breath held at total lung capacity (9,22). provides a useful indication of the inefficiency of After normalization, the regional distribution of ventilation by showing what proportion of each activity of the single breath is divided by the regional breath is wasted. Likewise, determination of the distribution of activity at equilibrium (which repre amount of physiologic shunting by using the shunt sents lung volume) to give regional ventilation per equation unit lung volume. In the dynamic methods, measurements of re Os C@02—Ca02 gional count rates are made continuously during a @5t C@O2—CvO2' washin of radioxenon to equilibrium and then during (where Os is shunt flow, Ot is cardiac output, and the washout while breathing air (23,24). Methods Ca02, Cv02, and Ci@O2are the oxygen contents of of “quantitating―these studies fall into two groups: arterial, mixed venous and end pulmonary capillary 1. Most commonly the time during the washout, blood, respectively) gives a useful indication of for the count rate to fall to 50% of the equilibrium wasted blood flow. count rate, is used as an expression of ventilation; Calculation of the alveolar-arterial oxygen-tension the longer the time the worse the ventilation. Modi difference and measurement of physiologic dead fications of this idea include the time to 50% or space and shunt provide an indication of the extent 90% of the equilibrium value during the washin, or of the failure to match ventilation and blood flow, measurements of the turnover time from the washout as well as providing a symbolic way of representing phase, which require knowledge of functional resid this in terms of additional or a right-to ual capacity and (7). left shunt. When studies of regional ventilation and 2. Lesscommonly,rate constantsare derived blood flow are combined to provide “functional―or from the regional washout curves. These may be ob “parametric―images of the ventilation-perfusion ra tamed by curve stripping, or by arbitrarily fitting a tios, it is sometimes possible to visualize where in straight line to a semilog plot of the first 50 or 60% the lung the major problem is situated. Such func of the washout curve, or by using the height/area tional images do not represent the real ventilation approach, which measures the mean rate constant. perfusion ratios. This is partly because it is most The quasistatic and dynamic methods are often unusual to measure alveolar ventilation and cardiac combined in a single study, starting with a single output during these studies, but more importantly breath, proceeding to equilibrium during a rebreath because the inequalities of ventilation and blood ing phase, and finishing with the washout study. flow are average values of the many lung units in the In studies in which the distribution of a single cores of tissue being viewed by the detector. The breath to total lung capacity is compared with that degree of ventilation-perfusion inequality detected by of lung volume (at total lung capacity), the results external counting considerably underestimates the indicate how much air entered a part of the lung in degree of inequality actually present in the lung. proportion to the local lung volume. For slow breaths the distribution will depend more on local compli TECHNIQUES TO STUDY REGIONAL VENTILATION ance than airway resistance, while for a rapid breath Studies of regional ventilation should permit an airway resistance will dominate the distribution (19). assessment of the effects of alterations in local com Since no exchange of air is determined, the results, pliance and airway resistance, as well as of lung vol strictly speaking, should not be referred to as yen ume (18). tilation. For instance in patients with obstructive Radioactive xenon is most widely used, but its airway disease, air may enter a region but may solubility in blood and tissue is a disadvantage when not be exchanged with any there before being ex measurements of regional ventilation are to be made pired (25) . If single-breath studies are to be used from washout curves. Nitrogen-i 3, which is consid clinically, the rate of inspiration should be con erably less soluble, serves as a standard for such trolled. measurements (20) , while krypton-8 im offers a new Measurements based on washin and washout stud approach to this problem (21). ies relate more closely to ventilation or the exchange

964 THE JOURNAL OF NUCLEAR MEDICiNE ADJUNCTIVE MEDICAL KNOWLEDGE of air. How much air is actually exchanged in a with early obstructive airways disease, pneumoconi breath depends on how large the breath is (i.e., on osis, ischemic heart disease, or cirrhosis of the liver tidal volume) , and also on how large the physiologic (27,29). In childhood, closing volume has been space is. The greater the VD/VT ratio, the smaller shown to overlap functional residual capacity at the the proportion of the tidal breath that is actually age of 6; it then decreases to unmeasurable levels exchanged. In measurements made over time, 5ev by the end of the second decade (30). eral breaths will take place, so that the frequency of Krypton-8 1m, with a half-life of only 13 sec, pro ventilation will also influence the rate at which equi vides a unique way of studying regional ventilation. librium is approached, and likewise the rate of Theoretical considerations suggest that during tidal clearance. breathing, an equilibrium is reached when the count Measuring the half-times of clearance—i.e., the rate is proportional to ventilation per unit lung time to 50% of the equilibrium activity—is a con volume. The relationship, moreover, is almost un venient and much-used way of expressing regional ear (21 ) . Excellent agreement has been found in ventilation. It must be distinguished from T112. The comparisons between measurements of regional yen T112 is derived from the clearance curve and is in tilation using xenon-i 27 or nitrogen-i 3 and krypton versely proportional to the rate constant (A), 8im. Furthermore, rapid changes in regional yen tilation may be studied, because equilibrium is 0.693 — ‘•I' reached within a minute or so of the change. I 1/2 and is usually determined from semilog plots of the TECHNIQUES TO STUDY REGIONAL washout data. PULMONARY BLOOD FLOW Measurement of the mean rate constants from Regional blood flow was first studied using C'502. washout curves gives an indication of the efficiency This gas is very soluble, and after is rap of , that is, what proportion of local idly removed from the lungs by blood flow, the rate lung volume is actually being used for exchange. For of clearance being proportional to blood flow (31). such calculations, the solubility of radioxenon in The less soluble gas radioxenon, or the even less blood and tissue must be considered, and the chest soluble gas radionitrogen, may also be used, but the wall and pulmonary-vascular contributions to the principle governing their use is different. These gases count rate should be allowed for, in order to obtain are dissolved in saline and given intravenously. As more realistic figures for regional ventilation (20,25). they reach the alveoli they come out of solution and Comparisons of the clearance of radioxenon and enter the alveolar air. During breath holding their of the less soluble nitrogen-i 3, measured from the distribution is proportional to blood flow. Krypton washout following equilibrium, have shown that the 8 im may be given by continuous i.v. infusion. The activity in the chest wall accounts for about 25% physical decay of this radionuclide is so rapid that of the difference in clearance rates, while the xenon its distribution is proportional to blood flow, which in the pulmonary vasculature accounts for the re enables rapid changes of pulmonary blood flow to maining 75% of the difference (26). be visualized almost instantaneously (21). The inhalation of boluses of radioxenon at dif Today studies of pulmonary blood flow usually ferent permits determination of the involve the i.v. injection of labeled particles of albu regional distribution of lung volumes and the re mm—either microspheres or macroaggregates. For gional distribution of different parts of a single in a reliable indication of relative blood flow, there must spiration. Similarly, radioxenon has been used to be enough particles (more than i 5,000 is adequate; measure closing volume, but this can be done as 60,000—150,000 plenty) and they must be properly accurately, and with no radiation to the patient, mixed with the blood stream to ensure that they are using either the single-breath nitrogen test (the resi accurately tracing blood flow. Mixing takes place as dent-gas technique) or boluses of other, nonradio the particles traverse both chambers of the right active tracer gases, such as argon or helium (27,28). heart before entering the Increases in closing volume merely reflect disease (32—37). processes affecting the small airways in a nonspecific, In infancy and childhood, the number and size though quite sensitive, fashion. of the pulmonary vessels are important considera (closing volume plus residual volume) increases with tions in determining the number of particles to in age and overlaps functional residual capacity in the ject. Too few will cause irregularities in the apparent seventh decade. It has also been shown to be in distribution, and too many can compromise the avail creased in apparently healthy (but often sympto able vascular bed. matic) cigarette smokers, in obesity, and in patients Because these particles are trapped in the termi

Volume 19, Number 8 965 SECKER-WALKER nal pulmonary arterioles and capillaries, their dis that ventilation of the affected region is preserved, tribution reflects pulmonary arterial blood flow to or clearly less impaired than blood flow (41,45). these regions (34). Another group of mechanisms relates to reduc When the relatively insoluble gases radioxenon tions in blood flow secondary to alterations in yen and radionitrogen are used, they give an indication tilation. The diseases collectively known as chronic of capillary blood flow to air-containing alveoli, par obstructive airway disease are the chief offenders ticularly those in the more proximal parts of the (46—49). primary lobules. Areas with pneumonic consolida Local is thought to play the major role tion, infarction, or atelectasis will appear to have no here. It is brought about by uneven ventilation, which blood flow using these gases. is due to local changes in airway resistance and corn@ pliance. As mentioned earlier, airway resistance may BASIC MECHANISMS UNDERLYING DISTURBANCES be increased by mucous plugs, , IN REGIONAL LUNG FUNCTION bronchial-wall thickening, or grossly distorted air The distribution of pulmonary arterial blood flow ways. Compliance will increase in emphysema, but is altered by changes in cardiac output, and also by diminish in other parenchymal processes. When the changes in resistance in the pulmonary arteries or diminution of blood flow is due to hypoxia, it can veins. An increase in cardiac output, such as occurs be altered favorably by administration of oxygen or in exertion, causes a more uniform distribution of . In some of these diseases, particu blood flow, with loss of the normal gradient. In larly emphysema, there is also loss of capillary bed, creases in resistance in the pulmonary vasculature leading to a further diminution in blood flow. may be brought about by changes in the vessels them Local bronchial obstruction by foreign bodies, selves, by changes in the lung parenchyma, or by tumors, or mucous plugs may also cause diminished elevations of left-atrial pressure. ventilation, with local hypoxia and a reflex local It should be remembered that alveolar hypoxia is diminution in blood flow. The local reflex vasocon a powerful vasoconstrictor of the pulmonary arteri striction that accompanies local hypoxia is some oles. Local pulmonary arteriolar constriction takes what variable and rarely reduces blood flow to the place in response to a diminished concentration, or same extent as the reduction in ventilation. Such pressure, of oxygen in the airway, but not in the regions have low ventilation-perfusion ratios, and blood (38,39). hence the blood leaving them is hypoxic. Atelectasis A number of disease processes directly affect the and pneumonic consolidation are extreme examples, pulmonary arterial tree, the commonest problem with no ventilation and greatly reduced blood flow. here being pulmonary embolism (37,40,41 ). Pulmo What blood flow there is acts as a right-to-left shunt, nary emboli, fat emboli, amniotic-fluid emboli, air causing hypoxemia. emboli, and others may all produce defects in blood The last mechanism is compression of the lungs by flow by partial or complete obstruction of pulmonary pleural effusions or large hearts. The apparent defect vessels. Pulmonary stenosis, pulmonary arteriove in blood flow and ventilation corresponds to the vol nous fistulae, pulmonary vasculitis, and the loss of ume of lung occupied by the fluid or the heart. pulmonary capillary bed in emphysema or interstitial It simplifies thinking about pulmonary diseases to fibrosis may all alter the distribution of pulmonary divide them into those in which the predominant arterial blood flow. effect is a diminution in static compliance and those Compression of the pulmonary vessels by tumor in which there is an increase in airway resistance. In or enlarged lymph nodes at the hilum, or tumor in both categories the process may be local or general. vasion of the pulmonary veins (which is usually For instance, compliance is diffusely reduced in con accompanied by thrombosis) and, much less corn ditions such as diffuse fibrosing alveolitis or pulmo monly, invasion of the pulmonary arteries may also nary edema, but locally reduced in pneumonia or cause changes in blood flow (42). atelectasis. Airway resistance is diffusely, but irregu Increases in left-atnal pressure in mitral stenosis larly, increased in , chronic bronchitis, and or left-ventricular failure cause a redistribution of emphysema, but locally increased in obstruction due blood flow from the bases towards the apices. For to a foreign body or large endobronchial tumor. the same elevation of left-atrial pressure, the redis In the restrictive lung diseases, measurement of tribution of flow is more marked in mitral stenosis regional ventilation and blood flow are generally of than it is in left-ventricular failure (43,44). little clinical value. They are considerably more use The underlying disease process can be localized to ful in obstructive airway disease, partly because early the pulmonary vasculature with considerable con disease is quite readily recognized but more espe fidence, but not complete certainty, when it is found cially for their help in the differential diagnosis of

966 THE JOURNAL OF NUCLEAR MEDICINE ADJUNCTIVE MEDICAL KNOWLEDGE suspected pulmonary embolism. Here the impact of tically significant, serve as useful reminders that these ventilation studies has largely been to show which tests are looking at different aspects of lung func patients had obstructive airway disease to account tion (25). for their abnormal perfusion scans, thereby improv ing both the sensitivity and specificity of the tech BOOKS nique (41). BouHuys A: Breoihing—Physiol6gy, Environment and Locally delayed clearance from the lungs means Lung Disease. New York, Grune and Stratton, 1974 locally impaired exchange of air, and this could be COMROE JH: Physiology of , Second Edition. due to local small-airways disease or a more proxi Chicago, Year Book Medical Publishers, Inc., 1974 mal partial or complete obstruction-complete at MOUNTCASTLE VB: Medical Physiology, Thirteenth Edi tion, Volume 2, Part XI, Respiration, St. Louis, CV Mosby, the segmental level because exchange can take place 1974,pp 1361—1597 between segments through the pores of Kohn. Wide WEST JB: Respiratory Physiology—The Essentials. Balti spread irregularly delayed clearance may be due to more, The Williams & Wilkins Company, 1974 generalized obstructive airway disease, but a similar appearance is seen in hypoventilation due to drug REFERENCES

overdose, or neurologic disorders such as myasthenia 1. HORSFIELD K, CUMMING G: Morphology of the bron gravis or peripheral neuropathies, or many other chial tree in man. I App! Physiol 24: 373—383,1968 causes of alveolar hypoventilation, including the 2. HORSFIELD K, CUMMING 0: Functional consequences Pickwickian syndrome. of airway morphology. I App! Physio! 24: 384—439 3. WEIBEL ER: Morphometry of the Human Lungs. New Increased clearance implies hyperventilation, and York, Academic Press, 1963 is likely to be seen in diseases in which compliance 4. Mau J, TAK.I5HIMAT, LErru D: Stress distribution is decreased, such as diffuse interstitial fibrosis, early in lungs: A model of pulmonary elasticity. I App! Physio! heart failure, and other causes of pulmonary edema. 28: 596—608,1970 5. MACKLEMPT: Airway obstruction and collateral yen Images obtained at equilibrium indicate the dis tilation. Physio! Rev 51: 368—436,1971 tribution of lung volume. In moderate to severe ob 6. BREEZERG, WII.EELDONEB: The cells of the pulmo structive airway disease, however, it is unusual to nary airways. Am Rev Respir Dis 116: 705—777,1977 reach equilibrium in 3—4mm (a time that is often 7. BALLWC, STEWARTPB, NEWSHAMLOS, et al: Re used for the washin, since longer times increase the gional pulmonary function studies with xenon@. I C!in lnvest4l: 519—531,1962 radiation burden), so that many so-called “equilib 8. BRYAN AC, BEr'rrivooLlo LG, BEEREL F, et al: Fac rium images― do not show the distribution of lung tors affecting regional distribution of ventilation and per volume. The uneven patterns seen in these situations fusion in the lung. I App! Physio! 19: 395—402, 1964 accurately reflect the worst-ventilated parts of the 9. DOLLERYCT, GILLAM PMS: The distribution of blood lung. Defects at the end of a washin will also be seen and gas within the lungs measured by scanning after ad ministration of “Xe.Thorax 18: 3 16—325,1963 with pneumonic consolidation, infarction, atelectasis, 10. KANEKOK, Miuc-EMILI J, DOLOVICHMB, et al: Re and pleural effusion. gional distribution of ventilation and perfusion as a func Whether single-breath or washout techniques are tion of body position. I App! Physio! 21: 767—777,1966 used, these tests measure aspects of lung function 11. MACKLEM PT, MEAD J: Resistanceof central and that are different from regular pulmonary function peripheral airways measured by a retrograde catheter. I App! Physio!22: 395—401,1967 tests such as Forced , Forced Expira 12. MILLErFE B, ROBERTSON PC, Ross WRD, et al: Ef tory Volume in one second, and airflow rates. The fect of expiratory flow rate on emptying of lung regions. Forced Vital Capacity is after all a forced maneuver, I App! Physic! 27: 587—591, 1969 an attempt to study the patient's maximum perform 13. INGRAM RH, O'CAIN CF: Frequency dependence of ance at this time, while a washin-washout study is compliance in apparently healthy smokers versus non smokers. Bul! Physiopatho! Respir 7 : 195—210,1971 done during resting tidal breathing and reflects the 14. WEST JB, DOLLERY CT, NAIMARK A: Distribution of usual exchange of air in the alveoli. blood flow in isolated lung: relation to vascular and al In children with cystic fibrosis, the whole-lung veolar pressures. I App! Physio! 19: 7 13—724,1964 clearance of radioxenon has been shown to be cor 15. HUGHES JMB, GLAZIER JB, MALONEY JE, et al: Effect related with Forced Expiratory Volume at 1 sec and of lung volume on the distribution of pulmonary blood flow in man. Respir Physio! 4: 58—72,1968 Peak Flow Rates (50) . In adults with obstructive 16. ANTHONISENNR, MILIc-EMILI 1: Distribution of airway disease, the whole-lung clearance has been pulmonary perfusion in erect man. I App! Physiol 21 : 760— correlated with Forced Expiratory Volume at 1 sec 766, 1966 and Maximum Mid-flow Rate, less well with ratios 17. WEST JB: Pulmonary function studies with radio active gases. Annu Rev Med 18: 459—470,1967 of Forced Expiratory Volume-1-to-Forced Vital Ca 18. WEsT JB : Ventilation/Blood Flow and Gas Exchange. pacity, and with PaCO2 but not Pa02. The correla Oxford, Blackwell, 1970 tion coefficients are 0.7 or less and, although statis I 9. MILIc-EMILI J : Radioactive xenon in the evaluation

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of regional lung function. Semin Nuci Med 1: 246—262, 35. TAPLIN GV, JOHNSON DE, D0RE EK, et al: Lung 1971 photoscans with macroaggregates of human serum radio 20. MArFHEWS CME, DOLLERY CT: Interpretation of albumin. Experimental basis and initial clinical trials. @“Xelung wash-in and wash-out curves using an analogue Health Phys 10: 1219—1227,1964 computer.ClinSci28: 573—590,1965 36. TAPLIN GV, MACDONALD NS: Radiochemistry of 21. FAzIo F, JONES T: Assessment of regional ventila macroaggregated albumin and newer lung scanning agents. tion by continuous inhalation of radioactive Krypton-81m. SeminNuc!Med 1:132—152,1971 BritMedl3: 673—676,1975 37. WAGNER HN, SABISTON DC, MCAi'EE JO, et al: 22. GLAZIER JB, DEN@uwo GL: Pulmonary function Diagnosis of massive pulmonary embolism in man by radio studied with the xenon― scanning technique. Normal val isotope scanning. N Eng I Med 271 : 377—384,1964 ues and a postural study. Am Rev Respir Dis 94: 188—194, 38. ARBORELIUS M, LILJA B: Effect of sitting, hypoxia, 1966 and breath-holding on the distribution of pulmonary blood 23. MILLERJM, AL! MK, HOWECD : Clinical determi flow in man. Scand I Clin Lab Invest 24: 261—269,1969 nation of regional pulmonary function during normal breath 39. GLAZIER JB, MuiuuY JF: Sites of pulmonary vaso ing using xenon 133. Am Rev Respir Dis 101 : 218—229, motor reactivity in the dog during alveolar hypoxia and 1970 serotonin and histamine infusion. I C!in invest 50: 2550— 24. MIöRNERG : 1―Xe-radiospirometry. A clinical method 2558, 1971 for studying regional lung function. Scand J Respir Dis 49: 40. POULOSE KP, REBA RC, GILDAY DL, et al: Diagnosis Suppl No 64, 5—84,1968 of pulmonary embolism. A correlative study of the clinical 25. SECKER-WALKER RH, ALDERSON P0, WILHELM J, scan, and angiographic findings. Br Med I 3: 67—71, 1970 et al: The measurement of regional ventilation during tidal 41. ALDERSONP0, RUYANAVECHN, SECKER-WALKERRH, breathing: a comparison of two methods in healthy sub et al: The role of @‘Xeventilation studies in the scintigraphic jects, and patients with chronic . detection of pulmonary embolism. Radiology 120: 633— BritlRadiol48:181—189,1975 640, 1976 26. RONCHETTI R, EWAN PW, JONES T, et al : Proceed 42. SECKER-WALKER RH, PROVAN JL, JACKSON JA, et al: ings : Use of 13N for regional clearance curves compared Lung scanning in carcinoma of the . Thorax 26: with 1―Xe.Bull Physiopaihol Respir 11: 124P—125P,1975 23—32,1971 27. BUIST AS, VAN FLEET DL, Ross BB : A comparison 43. DOLLERY CT, WEST JB: Regional uptake of radio of conventional spirometric tests and the test of closing active oxygen, carbon monoxide and carbon dioxide in the volume in an emphysema screening center. Am Rev Respir lungs of patients with mitral stenosis. Circ Res 8 : 765—771, Dis 107:735—743,1973 1960 28. HOLLAND J, MILIc-EMILI J, MACKLEM PT, et al: 44. FRIEDMANWF, BRAUNWALDE: Alterations in regional Regional distribution of pulmonary ventilation and perfu pulmonary blood flow in mitral valve disease studied by sion in elderly subjects. I Clin Invest 47 : 81—92,1968 radioisotope scanning. Circulation 34: 363—376,1966 45. DEN@uwo GL, GooDwiN DA, RAVASINI R, et al: The 29. RUFF FJ, COUTURE J, MILIc-EMILI J: Closure of peripheral airways : Demonstration by regional studies of ventilatory lung scan in the diagnosis of pulmonary em bolism. N Eng! I Med 282: 1334—1336,1970 “Xe clearance. In Dynamic Studies with Radioisotopes in 46. BENTIVOGLIOLG, BEERELF, BRYANAC, et al: Re Medicine, International Atomic Energy Agency, Sympo gional pulmonary function studied with 1―xenonin patients sium, Vienna, pp 809—817,1970 with bronchial asthma. I C!in invest 42: 1193—1200,1963 30. MANSELL A, BRYAN C, LEVINSON H : Airway closure 47. BENTIVOGLIOLG, BEEREL F, STEWARTPB, et al: in children. I App! Physio! 33: 711—714,1972 Studies of regional ventilation and perfusion in pulmonary 31. Wrsr JB, DOLLERY CT: Distribution of blood flow emphysema using xenon'@. Am Rev Respir Dis 8 : 315—327, and ventilation.perfusion ratio in the lung, measured with 1963 radioactive CO2. I App! Physiol 15: 405—410,1960 48. HECKSCHERT, BAss H, OnioL A, et al: Regional 32. HECK LL, DULEY JW : Statistical considerations in lung function in patients with bronchial asthma. I Clin lung imaging with °@mTcalbumin particles. Radiology I 13: invest47: 1063—1070, 1968 675—679,1974 49. PAIN MCF, GLAZIER JB, SIMON H, et al: Regional 33. RHODES BA, STERN HS, BUCHANANJA, et al : Lung and overall inequality of ventilation and blood flow in pa scanning with “mTcmicrospheres. Radiology 99: 613—621, tients with chronic airflow obstruction. Thorax 22: 453— 1971 461, 1967 34. ROGERS RM, KUHL DE, HYDE RW, et al : Measure 50. ALDERSONP0, SECKER-WALICERRH, STROMINGERDB, ment of the vital capacity and perfusion of each lung by et al : Quantitative assessment of regional ventilation and fluoroscopy and macroaggregated albumin lung scanning. perfusion in children with cystic fibrosis. Radiology 111: Ann mt Med 67: 947—956,1967 151—155,1974

968 THE JOURNAL OF NUCLEAR MEDICINE