Ventiliation-Perfusion Relationships and Gas Exchange

SCOTT R. INKLEY, M.D. AND WILLIAM J. MacINTYRE, Ph.D.

Case Western Reserve University School of Medicine, University Hospitals, and the George M. Humphrey Cardio- Pulmonary Laboratory, Cleveland, OH 44106

Introduction pared to perfusion produces hypoxemia and The most common cause of hypoxemia at low or normal pC 02; in some instances it sea level is mismatched ventilation and per may also produce hypercapnia. fusion. Common clinical problems such as Until the development of radioactive gas pneumonia, pulmonary embolism, obstruc techniques for measurement of regional tive lung disease and many other diseases ventilation and perfusion by Knipping in produce regional hypoventilation as com 1953,3, V/Q ratios for the entire lung could pared to perfusion, resulting in incompletely be obtained but no methods were available oxygenated blood leaving the pulmonary to estimate these relationships regionally. capillary in hypoventilated regions and re Since that time, extensive research has been turning to the left heart. carried out by many investigators who have The relationship of ventilation to perfu used these techniques both for clinical de sion or Va/Qc refers to the turnover of air scription and for better understanding of in the alveoli (V A) compared to the flow of basic physiology of the lung. West and blood through pulmonary capillaries (Qc). others5 have described a V/Q mismatch in A V a/Q c of one would consist of one L of the normal upright subject where V/Q is air ventilating the alveoli and one L of higher at the apex than at the base. The blood flowing through the pulmonary capil net effect of this mismatch is not sufficient lary bed during the same period of time. to alter arterial p0 2 significantly, however. The measurement of overall VA/Q e in the These studies do, however, point out the human subject requires measurement of variation in regional perfusion dependent alveolar ventilation by the collection of on body position and change in ventilation expired air and measurement of arterial required to maintain adequate matching of p C 0 2 as well as measurement of cardiac ventilation to perfusion. Such matching output. This relationship is usually around avoids overventilation of portions of the 0.8. When total alveolar ventilation is in lung that are poorly perfused. Recent evi adequate for the needs of the patient, then dence has been obtained showing that hypoventilation causes hypoxemia and hy- measurements of ventilation and perfusion percapnia. In the clinical states mentioned, at resting lung volumes using clearance of the authors are interested in regional mis perfused 133Xenon during normal breathing match of ventilation and perfusion usually shows V/Q to be more evenly matched referred to as V/Q mismatch. Regional V/Q than was observed previously. 2 The prac mismatch or regional hypoventilation com tical clinical application of these methods

17 1 8 1NKLEY AND MACINTYRE

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RIGHT SIDE LEFT SI0E ************ *********** 40* UPPER 36*

11* LOWER 11* ************ *********** 52* TOTAL 47* F ig u r e 1. This shows a 40 X 40 matrix using a digital scale of 0-99 with the highest numbers representing the highest counting rates. The matrix illustrates the distribution of perfusion after an intravenous injection of 133Xenon during a breathhold at Functional Residual Capacity. in the diseased lung, however, brings up to what should have been deposited if all some problems that are not of great im the radioactivity had been distributed portance in the normal lung. equally in all alveoli. The index as defined In order to correct for volume variation by Ball et al1 is as well as variation in absorption of radio Ventilation Index = activity by body structures, it is necessary to calculate a ventilation or perfusion index Single Breath Regional Activity utilizing information obtained after the lung Single Breath Total Lung Activity has come to equilibrium with radioactive Steady State Regional Activity gas contained in a spirometer. This index Steady State Total Lung Activity is a ratio of what is actually deposited in = Vr/V t a given region, by perfusion or inhalation, E r/E t VENTILATION-PERFUSION RELATIONSHIPS AND GAS EXCHANGE 1 9

Perfusion Index = Perfusion Regional Activity Perfusion Total Lung Activity Steady State Regional Activity Steady State Total Lung Activity

_ Q r /Q t GAS EXCHANGE POTENTIAL (GEP1 SCALE= 65 w r x - 9« E r /E t This is not a difficult achievement in the normal lung where all alveoli are presum ably evenly ventilated. In the diseased lung, however, equilibrium may be difficult if not impossible to obtain and matching ventila tion and perfusion indices impossible to calculate. SLOPES SCflLE= 6 5 » w h The use of radioactive techniques of mea suring perfusion and ventilation promises to offer important contributions to the mea surement of regional lung function in the normal. In the abnormal subject, measure ment of perfusion and clearance by injec tion of 133Xenon in saline and its clearance from the alveoli by normal breathing (ven Ï - INTERCEPT SCPILE= ES hhm > m tilation ) offers an approach to the quantita tion of regional lung function in the dis F i g u r e 2. A 3-dimensional representation of the eased lung. digital information seen in a matrix. These are drawn by a computer driven plotter. Both lungs are visualized in the model and are viewed down Methods the lung from the apex. The lower model represents perfusion with high sites representing heavy per Perfusion of the lung can be measured fusion and low sites poor perfusion. This is a nor with intravenously injected macroaggre mal upright subject. Note the increased perfusion at the lung bases over the apex in the upright gated human serum albumin labeled either position. The middle model represents clearance with 131Iodine or " “Technetium or with with the Z axis representing the slope of clearance 133Xenon injected intravenously in solution. (ventilation). High sites in the model clear more rapidly than low. In the upper model regional gas In the first instance, the intensity of radio exchange ( perfusion X clearance ) is illustrated. activity is related to the tagged albumin that has been strained out in the pulmonary the patient in several different projections capillary bed. In the second, Xenon, a such as lateral, oblique, etc. This advantage highly insoluble gas, is 95 percent cleared also represents a potential disadvantage in in its passage through air containing alveoli. that the study cannot be repeated in dif The advantages of labeled albumin are that ferent positions and at different breath- it identifies sites that are perfused but con holds. The advantage of the Xenon is that tain no alveolar air and thus can identify it behaves as a gas and can be used to mea perfusion of totally non-air containing al sure not only perfusion but clearance (or veoli, such as in pneumonia. The radioac ventilation) from the alveolus. When la tivity remains in the pulmonary capillaries beled albumin is used, ventilation must be for a number of hours, permitting study of measured by the inhalation of tagged gas 2 0 INKLEY AND MACINTYRE

F i g u r e 3 . The left hand models illustrate perfusion, clearance and gas exchange at Func tional Residual Capacity; the right hand models the same patient studied at Total Lung Capacity. Note the change in per fusion of the left lung between two different breathholds. Clearance is essentially non-existent from the left lung when at TLC and gas exchange is therefore absent in the left lung. This patient had a carcinoma of the left hilum.

T-INTERCEPT SCALE- 6S . m y-intercept schce- tz « from a spirometer. It is impossible, how a more reliable index of ventilation in the ever, to be sure that gas inhaled from a abnormal lung. spirometer and measured outside the chest Radioactivity can be measured either by a radioactive detector is in conducting with multiple probes or with a gamma airways or alveoli. For this reason, the mea camera which permits visualization of most surement of clearance would seem to offer of the chest simultaneously. The use of the multi-detector method requires the calcula UPRIGHT tion of indices of ventilation and perfusion by the method of Ball1 and samples larger regions, from the point of view of resolu tion, than the gamma camera. When the camera is used, values for ventilation and perfusion can be normalized and regional ratios easily derived. r-JNTERCEPT SCflLE= 65 win*, as Newer instrumentation permits the re cording of digital information from multi SUPINE ple sites on a memory device at time in tervals so that dynamic studies of clear ance can be done. Such data can be proc essed by computer and clearance curves calculated for multiple sites.4 In our studies, the slope of clearance of the first 60 percent of the amount cleared is calculated by the r-JNTERCEPT SCflLE= SS max» sa method of least squares. Knowing the per F i g u r e 4. A patient with biopsy proven basalar fusion of a site and the rate of clearance interstitial fibrosis. Note the difference in perfusion of the bases between upright and supine, presum or ventilation of that site, it is possible to ably due to the interstitial disease. estimate gas exchange or, by multiplying VENTILATION-PERFUSION RELATIONSHIPS AND GAS EXCHANGE 2 1 perfusion X clearance = regional gas ex change. Sites with good perfusion and slow clearance are less capable of gas exchange than sites of good perfusion and rapid clear ance. From a single injection study done at resting lung volumes followed by quiet breathing, one can calculate regional perfu sion, regional clearance (ventilation), and regional gas exchange. In our studies, a matrix 40 X 40 (figure 1) has been used providing 1,600 sites where these values can be recorded. Because it is difficult to look at a mass of numbers, a computer drawn three dimensional model (figure 2) has been used where the Z axis represents the amount of regional perfusion, slope of the washout curve or amount of regional gas exchange.

Discussion When radioactive techniques are used to measure regional function it may be of value to measure perfusion and ventilation at resting lung volumes and at total lung capacity as well as supine and erect. The effect of lung volume at the time of injec tion is illustrated in figure 3 where the left lung was essentially nonperfused at resting lung volumes and showed no clearance and no gas exchange. At maximum inspiration (Total Lung Capacity), the left lung be came perfused but did not clear the radio activity during quiet breathing. Gas ex change in that lung continued to be F i g u r e 5. A patient with cystic fibrosis. The negligible. lower model shows the distribution of inhaled The effect of body position is illustrated 133Xenon to be rather uniform. Perfusion (Q in tercept) shows some rather non-homogeneous dis in another patient who had biopsy proven tribution of perfusion in both right and left lung. interstitial fibrosis. In the upright position Clearance (slopes) shows an entirely different pic ture in the right lung than is seen in the ventila perfusion of the bases was fairly normal tion study. Regional gas exchange is markedly (figure 4) whereas perfusion decreased to reduced in the right lung. almost nothing at the base when the patient was supine. readily apparent that regions that appear The difference between ventilation mea to be well ventilated when Xenon was in sured by inhalation and ventilation mea haled from a spirometer failed to show sured by clearance is illustrated in figure 5. normal clearance in the post injection study. This patient had cystic fibrosis, and it is This suggests that there may have been 2 2 INKLEY AND MACINTYRE

ASTHMA

DURING ATTACK AFTER ATTACK

CAS EXCHANGE POTENTIAL (CEP) GAS EXCHANGE POTENTIAL (GEP) SCALE = 65 NMAX = 98 SCALE - 65 NMAX = 98

F i g u r e 6. A patient during and after an asth matic attack was studied in the upright position. SLOPES SCALE = 65 NMAX - 98 SLOPES SCALE = 65 NMAX = 98 Not the reduced perfu sion (Y intercept) in the left lung and the in creased perfusion of the right lung during the at tack. In this instance, clearance and ventilation match very well. Y-INTERCEPT SCALE - 65 NMAX = 98 Y-INTERCEPT SCALE = 65 NMAX » 98

ASTHMA

VENTILATION STUDIES

DURING AFTER ATTACK ATTACK

STATIC DISTRIBUTION SCALE = 44 STATIC DISTRIBUTION SCALE = 16 NMAX « 66 NMAX = 29 small airways obstruction that was not both lung fields, and the Xenon scan shows readily identified. regions of decreased perfusion, ventilation, Another subject with acute asthma was and gas exchange similar to the infiltrates seen to perfuse the upper lungs better than seen in the X-ray. Pulmonary function would be expected in the upright position studies during the early management of this (figure 6). Ventilation and clearance of the patient showed restrictive disease and se poorly perfused areas were seen to be mark vere gas exchange problems manifested by edly reduced. This is an illustration of reflex high A-a gradients. Following treatment, homeostasis in which perfusion and ven the X-ray and function studies returned to tilation tend to match one another in the normal, but regions of decreased gas ex pathological state. A repeat study during change coidd still be identified on the scan. an interval when the patient was relatively asymptomatic showed a more normal dis Sum m ary tribution of both ventilation and perfusion. The use of radioisotope techniques to Another patient is illustrated in figure 7 measure regional perfusion and ventilation with biopsy proven sarcoid. The chest X-ray represents a significant step forward in the ( figure 8) shows large nodular infiltrates in identification of regional alteration of func VENTILATION-PERFUSION RELATIONSHIPS AND GAS EXCHANGE 2 3 tion. The use of macroaggregated albumin SARCO ID has the advantages of identifying the capil lary bed even though it flows through non aerated alveoli and offers the advantage of scanning in a number of different positions after one injection. Xenon, when injected and used to mea sure perfusion and clearance, has the ad GAS EXCHANGE POTENTIAL (GEP) SCALE = 65 NMAX - 98 vantage that it behaves as a gas and mea sures radioactivity in perfused air containing alveoli. When the gas is cleared from alveoli, there is no question that the radio activity in the lung may be in conducting airways rather than alveoli. Ventilation measured in this manner is, therefore, SLOPES SCALE = 65 NMAX - 98 alveolar ventilation. Although it does not offer the advantage of multipositional scans after a single injection, it does make pos sible various positions and breathholds at the time of injection. The calculation of indices of perfusion and ventilation requires the evaluation of lung size after breathing to equilibrium. In the diseased lung, it may be impossible to achieve equilibrium because of the radia tion exposure required to ventilate slow spaces in the lung, or it may be that some areas of the lung are totally unidentifiable owing to total airway obstruction or com plete filling of the alveoli with fluid or exudate. V /Q ratios, therefore, seem to have F i g u r e 7. A subject with sarcoid who showed many practical disadvantages so far as rou great variation in regional perfusion, clearance and tine clinical application is concerned since, gas exchange. The regions of reduced perfusion and gas exchange correspond with the areas of even with the camera, ventilation is not x-ray infiltrate. assuredly in the alveoli. The primary use of regional studies of ventilation-perfusion and gas exchange in sure regional perfusion, clearance (ventila clinical medicine is to evaluate regional tion ) and gas exchange offer the most direct disturbance of gas exchange for one of three and practical approach to the problem. The purposes: (1) early detection of disease, complicated techniques involved do present (2) preoperative evaluation to avoid resec a problem for even the medium sized in tion of important gas exchanging portions stitution. However, the ready availability of the lung, and (3) better understanding of much of the equipment in isotope labora of disturbed regional physiology in the tories of many hospitals and the increased study and evaluation of a disease process access to computers, either in the hospital and/or its treatment. It is felt that the tech or on a long distance time sharing plan, niques described, using 133Xenon to mea promises to make these approaches more 2 4 IN'KLEY AND MACINTYRE

F i g u r e 8. X-ray of subject in figure 7 show ing nodular sarcoid con firmed by biopsy and subsequent course.

feasible both technically and economically 3. S n ip p in g , H. W ., L u d e s , H., V a l e n t i n , H., in the near future. and Venrath, H.: Beitrag zur Differenzierung der Insuffizienz des linken, des rechten Heizens und der Lungen nebst Bemerkungen zur Her- R efe re n c es zondierung und zum Defizitproblem. Med. Klin. 6:161, 1953. 1. B a l l , W. C., S t e w a r t , P. B., N e w s h a m , L. G. 4. M acIntyre, W. J., I n k l e y , S. R ., R o t h , E., S., and Bates, D. V.: Regional pulmonary func D r e s c h e r , W. P., and Ishii, Y.: Spatial record tion studied with l33Xenon. J. Clin. Invest. 41: ing of disappearance constants of 133Xenon wash 519-531, 1962. out from the lung. J. Lab. Clin. Med. 76:7 0 1 - 2. Inkley, S. R. and M acIntyre, W. J.: Dynamic 702, 1970. measurement of ventilation-perfusion with 5. W e s t , J. B.: Ventilation/Blood Flow and Gas 133Xenon at resting lung volumes. Amer. Rev. Exchange. Blackwell Scientific Publications, Ox Resp. Dis. (in press). ford, 1965.