Pulmonary Ventilation*

Blood Flow Relationships in Interstitial Disease of the Lungs

JOHN READ, M.D.~. and R. S. WILLIAMS, M.B.

London, England

P ATHOLOGICAL thickening of the pulmonary alveolar walls interferes with diffusion of

gases between alveoli and capillaries. This dif- fusion defect, and the limitations imposed by decreased lung compliance and restricted lung volumes, are widely recognized as the major functional disturbances accompanying inter- stitial pulmonary disease [ 1-41.

Rather less attention has been paid to local disturbances of ventilation and blood flow within the lungs in interstitial disease. Motley [5] has recently produced indirect evidence that ventila- tion-perfusion imbalance probably occurs in many cases, but Donald and his colleagues [/I, after demonstrating such a ventilation-perfusion inequality, concluded that it was more apparent than real. As far as the more readily measured factor of uneven ventilation is concerned, re- ports are more numerous but conflicting. Baldwin et al. [Z] were unable to demonstrate abnormalities of regional ventilation in thirty- nine cases of pulmonary fibrosis. Bates [6] regarded any “mixing defect ” in cases of the Hamman-Rich syndrome as minimal, and he and his colleagues [4] found no unevenness of ventilation in most cases of diffuse pulmonary sarcoidosis. “Normal distribution of inspired gases” was regarded as one of the features of the alveolar-capillary block syndrome in a recent review [7]. Read [8], on the other hand, demon- strated uneven pulmonary ventilation in three of six cases of diffuse pulmonary fibrosis and three of five cases of diffuse pulmonary sarcoidosis.

The development of a respiratory mass spectrometer [9] which allows continuous analy- sis of up to four components of a gas mixture led to the introduction of a single-breath test of inequality of ventilation, perfusion and ventila- tion ratio [IO, 771. Here we report the results of

this single-breath test in a group of patients with interstitial lung disease.

SUBJECTS

Twenty-eight subjects were studied. Twenty-two were suffering from pulmonary asbestosis, which is known to produce interstitial pulmonary fibrosis [72] and a state of alveolar-capillary block [73]. Six were suffering from other conditions (one sarcoidosis, one scleroderma, one carcinomatosis, one Harmman-Rich syndrome, and two unknown disease). In all, the diffusion capacity for carbon monoxide was reduced.

The twenty-eight patients were divided into two groups, Group I, those with apparently pure interstitial disease; and Group II, those in whom the process was probably complicated by bronchial disease or emphy- sema. The “complicated” group consisted of those in whom the forced expiratory volume over 1 second was reduced to less than 70 per cent of the forced vital capacity (F.E.V.i.o/F.V.C. < 70 per cent [75]), and those whose chest roentgenogram showed obvious cysts (eleven patients). The remaining seventeen pa- tients were regarded as suffering from “pure” interstitial disease.

TECHNICS

West and Hugh-Jones (unpublished) have modified their original single-breath test [70,77] and the modi- fied technic was used in the present studies. The pa- tient sat in a comfortable chair, breathing quietly through the mouth from a valve-box which had a dead space of about 5 ml. The tip of the mass spectrometer sampling tube lay about 2 cm. from the lips, so that a continuous record of the composition of gas passing that point was obtained.

At the end of a normal expiration, the valve-box was switched into a spirometer circuit from which the patient made a maximal inspiration of a gas mixture containing 15 per cent argon, 20.9 per cent oxygen, and the remainder nitrogen. He then made a maximal expiration at moderate speed. Throughout the pro- cedure the mass spectrometer was adjusted to record

* From the Department of Medicine, Post-Graduate Medical School of London, London, W. 12, England. t Wunderly Travelling Scholar, Royal Australasian College of Physicians. Present Address: Department of Medicine,

University of Sydney, Sydney, Australia.

OCTOBER, 1959 545

Ventilation-Perfusion Relationships--Read, Williams

a “t 60

t

VENTILATION PERFUSION RATIO

VENTILATION

‘-I

PERFUSION .I.

VOLUME EXPIRED- LITRES

FIG. 1. Inequalities of ventilation-perfusion ratio, ven- tilation and perfusion in seventeen cases of pure inter- stitial disease. Each continuous line represents the change in that function for one patient traced through expiration (up to 2,500 ml.). The dotted lines enclose the range of normal values seen up to age fifty-five.

continuously the changing tensions of oxygen and carbon dioxide, and argon concentration. The expired volume was recorded concurrently on the fourth channel of the direct-writing recorder by integration of the signal from a wire-mesh flow-meter.

From the oxygen and carbon dioxide tensions at successive points in expiration in the resultant record, it is possible to calculate the respiratory quotient and hence the ventilation-perfusion (VA/&) ratio at those points, making use of the oxygen-carbon dioxide diagram of Rahn and Fenn [27]. From the argon concentration curve, the alveolar ventilation (V_.&‘, L. per unit time per L. of alveolar volume) at these same points is measured. The corresponding pul- monary blood flow values (Qc/VA L. per unit time per L. of alveolar volume) are calculated indirectly by dividing ventilation (V,/V,) by ventilation-per- fusion ratio (VJ(ie) at each point. Alveolar volume in each case is the volume at the resting expiratory level, Full details of the basis of these calculations are

given in the original report of the technic [70,77]. The changes in each function (ventilation, blood flow and ventilation-perfusion ratio) can then be plotted against expired volume. (Fig. 1.) The slope of the resulting line represents the unevenness of ventilation, blood flow or ventilation-perfusion ratio throughout the lungs. The steeper the slope the greater the unevenness of that particular function in different parts of the lungs.

In the original description this slope was expressed as the percentage change over 1 L. of expirate from 300 to 1,300 ml. expired. In the modified technic the point of reference is taken as the value of ventilation, perfusion or ventilation-perfusion ratio at 750 ml. expired (postdead space with maximal inspiration). The slope is then expressed as the percentage change for each 500 ml. expired from 750 ml. to the end of expiration. The greater the figure for inequality, the more uneven is ventilation, perfusion or ventilation- perfusion ratio throughout the lungs.

Each determination was performed in duplicate and the means calculated. The results were compared with normal standards from this laboratory [76] (approxi- mate upper limits of normality depending upon age; ventilation inequality 6 to 14 per cent; perfusion inequality 5 to 12 per cent; ventilation-perfusion ratio inequality 6 to 9.5 per cent).

The diffusion capacity for carbon monoxide (Doe) was determined by the modification of the Krogh breath-holding technic described by Ogilvie et al. [77]. The Do0 was measured in all but one patient, a man with diffuse pulmonary sarcoidosis who was short of breath, but who had a normal maximum breathing capacity. The Dco in each patient was reduced below the lowest limit of normal for his body surface area. For comparison between subjects the Dco in each case was expressed as a percentage of the mid-point of the normal range for that subject by the standards of Ogilvie et al. 1771.

RESULTS

Group I. Patients with Pure Interstitial Disease (Table I). Four patients (Cases 3, 5, 8 and 9; Table I) had ventilation, blood flow, and ventila- tion-perfusion ratio inequalities within normal limits. The remaining thirteen showed ab- normalities of one or more function. Twelve patients had uneven ventilation outside the range seen in normal subjects, and in some cases this unevenness of ventilation was very large. (For comparison, in severe emphysema, values for inequality of ventilation may reach 35 to 40 per cent per 500 ml. [IS].) Blood flow inequality remained within normal limits in every case. Twelve subjects had abnormal inequality of ventilation-perfusion ratio. There were no differ- ences between the patients with pulmonary

AMERICAN JOURNAL OF MEDICINE

Ventilation-Perfusion Relationships--Read, Williams

TABLE I TABLE II

VENTILATION, PERFUSION AND VENTILATION-PERFUSION VENTILATION, PERPUSION AND VENTILATION-PERPUSION . . . .

(VA/Qc) RATIO INEQUALITIES COMPARED WITH

Dco IN SUBJECTS WITH PURR INTERSTITIAL

DISEASE

(VA/QC) RATIO INEQUALITIES COMPARED WITH

Dco IN SUBJECTS WITH COMPLICATED

INTERSTITIAL DISEASE -

==

-_

-

T

I

-

T -

-

Inequality % per 500 ml. Expired

Inequality % per 500 ml. Expired DCO*

CFtX No.

- __

Abs. %

- I

9.9 9.8 9.4

10.3 13.8 11.2 11.9 15.7 13.1 13.8 13.3 16.8 17.2

8.4 12.0 13.0

-

37 39 40 41 47 48 49 53 58 60 63 66 12 37 49 51 .

- _-

- -

Ct3.W NO.

Age :Yr.)

59 46 46 55 45 45 54 52 54 56 57

Per- fusion

5=

21.9x -5.5x

17.5x 14.8X a.7

12.0x 9.0 0.3 7.9

22.1x 1.1

8.7

10.5 12

Age (yr.)

-

57 56 64 52 43 50 59 47 48 44 37 41 51 59 56 71 33

-

45

55 65

Venti- lation

- -

Venti- Per- CA/&

Iation fusion Ratio?

16.2X 22.1 x 11.8 16.3X

6.7 14.1 X 14.2X a.1 7.9

11.7x 23.4 X

8.6 17.6 X 21.6X 16.2 X 18.5 X 11.5x

13.1 x 17.1 x

7.1 17.8X

4.0 9.9 x 9.8 x 51 6.9 7.5

20.5 X 9.1 x

12.0x 19.1 x 12.7 X 10.7 x

9.7 x

IO

12 14

4.3 7.3 8.0

-2.4 3.8 5.7 7.1 4.0 1.1 4.4 5.3

-1.3

6.9 3.3 4.6 9.1 3.4

___ --

-

a.7

10.5 12

--

-

7.5

8.5 9.5

+A/(& Ratiot

Abs. %

O$ 6.4 30 8.7 35 9.3 38

10.2 39 12.4 43 12.8 53 14.4 56 10.4 67

5.8 26 14.0 48 __-

.

. . . . _... . .

35.8 x 36.3 X 30.0 x 19.1 x 10.3 x 15.4 x 11.2 11.9x 10.3 42.6 X 15.3 x

10

12 14

1. 2. 3. 4. 5. 6.

lg.6 X 39.9x 18.2 x

7.2 2.9 7.6 4.3

11.8 x 3.6

23.4X 14.2 X

7.5

8.5 9.5

1. 2. 3. 4. 5. 6. 7. 8. 8.

9. 10.

9. 10. 11. 11.

12. For Comparison:

Upper limits of normality at age

45

55 65

13. 14. 15. 16. 17.

Upper limits of normality at age:

Nmx: Casa 1 to 9, asbestosis; Cases 10 and 11, other interstitial dineaae.

*Dco: abs. = ml. CO/minute/mm. Hg partial pressure gradi- ent.

% = expressed as percentage of mid-point of normal range for that subject.

NOTE: Cases 1 to 13, asbcstoais; Cases 14 to 17, other interstitial t X: abnormal values (compared with normal subjects of same age, diiCt3SC. see text).

* Dco: abs. = ml. CO/minute/mm. Hg. partial pressure gradient % = expressed as percentage of mid-point of normal range

for that subject.

$ DCO so LOW as to bc unmeasurable by single-breath technic.

t X: abnormal value (compared with normal subjects of same age, see text).

Group II. Patients with Complicated Interstitial Disease (Table II). There was no constant pat- tern of abnormality in this group. Two patients had completely normal values. Some fell into the same pattern as those in the pure interstitial group, but the most striking feature was the presence of an abnormal inequality of blood flow, in six cases which was very large in five cases. The ventilation-perfusion ratio inequality was thus the resultant of the two disordered functions of unequal ventilation and perfusion in these cases, and did not bear the same close relationship to ventilation inequality that was seen in cases of uncomplicated interstitial disease.

COMMENTS

Analysis of a single expirate reveals inequality of ventilation, perfusion, or ventilation-perfusion ratio only if regions of lung with different ventilations or ventilation-perfusion ratios empty asynchronously. If all areas empty synchronously the alveolar plateau will be flat no matter what regional inequalities are present. This concept

asbestosis and those with other interstitial disease.

Excluding four patients (Cases 3, 5, 8 and 9) in whom all values were normal, and one patient (Case 12) who had an isolated inequality of ventilation-perfusion ratio, there remain twelve subjects in whom the ventilation-blood flow relationships fell into a remarkably constant pattern. This consisted of abnormal unevenness of ventilation, associated with even blood flow, with the result that the ventilation-perfusion ratio inequality was of the same order as the ventilatory inequality. This relationship is repre- sented graphically in Figure 1. It is confirmed by the high correlation (r = 0.904) between ventila- tory inequality and ventilation-perfusion ratio inequality.

Unevenness of ventilation did not run closely parallel with the severity of the diffusion defect (correlation coefficient between Dco and ven- tilatory inequality = -0.203).

OCTOBER, 1959

Ventilation-Perfusion Relationships--Read, WGzms

of “effective synchrony and asynchrony” of emptying has been amplified by West [78], who points out that the measured inequalities will be minimum ones. Still greater inequalities than those demonstrated may be hidden by the syn- chronous emptying of areas of lung with different ventilations or different ventilation-perfusion ratios. The synchrony of emptying cannot, how- ever, artificially increase true ventilation, per- fusion, or ventilation-perfusion ratio inequalities.

Similarly, it may be shown that, in interstitial disease, the presence of a diffusion defect will lead to an underestimate of the ventilation-per- fusion ratio inequality. In calculating the

VA/& ratio of any area with the present technic, it is assumed that there is no end- capillary gradient for oxygen or carbon dioxide. The presence of a constant end-capillary gradi- ent in all areas does not greatly affect the value . . of V_,JQc inequality. But regions with a low

GA/& ratio have a greater end-capillary

gradient than regions with a high VA/&Y ratio;

and this leads to a falsely high value for VA/& ratio in regions of the lung in which this ratio is low. Differences between areas with low and

high VA/& ratios will thus be artificially reduced, and we derive an underestimate of the true ventilation-perfusion ratio inequality. The presence of an especially large local diffu-

sion defect in the areas of low VA/& ratio will still further exaggerate this factor. The calcula- tion of alveolar ventilation from the argon tracing will not be affected, and the blood flow inequality may therefore be overestimated. The over-all effect in the present series is thus likely to be an underestimate of true ventilation and ventilation-perfusion ratio inequalities, and perhaps an overestimate of the inequality of perfusion.

These criticisms applied to the results in cases of pure interstitial disease would only serve to strengthen the pattern demonstrated in most cases: unevenness of ventilation and of ventila- tion-perfusion ratio in the presence of fairly uniform blood flow. In simple mechanical terms: Blood emerging from the right side of the heart is distributed evenly to all parts of the lungs. Inspired air is not evenly distributed. Some parts of the lungs receive a great deal more than others. As a result, the ratio of alveolar ventila- tion to alveolar perfusion varies markedly in different regions of the lungs.

Donald and his associates [7] concluded that

the major part of the ventilation-perfusion ratio inequality which they demonstrated in cases of pulmonary fibrosis with alveolar-capillary block was more apparent than real. Unevenness of perfusion, with absence of blood flow in some ventilated areas, played a small part. To account

for the larger part of the demonstrated VA/& inequality they postulated the presence of local areas with such a severe diffusion defect that gaseous exchange in these areas was grossly reduced. Blood from such regions would then have the characteristics of blood from an area of low ventilation-perfusion ratio, and gas from such regions would appear to come from areas with a high ventilation-perfusion ratio, although both ventilation and perfusion of these regions were actually normal.

The results of the present series of experiments suggest a different interpretation. The sloping ventilation-perfusion ratio lines in Figure 1 could be produced by a genuine ventilation- perfusion ratio inequality or by the mechanism which Donald et al. postulate. However, their hypothesis requires that ventilation shall be fairly even, and from the ventilation lines of Figure 1 (which are dependent purely on argon dilution and are not subject to the diffusion fac- tor) this is clearly not so. Quite apart from any questions of synchronous or asynchronous emptying, it is apparent from Figure 1 that regions with a high ventilation-perfusion ratio have a high ventilation and vice versa. We have seen, indeed, that throughout the pure interstitial

group, unevenness of ventilation-perfusion ratio is closely correlated with unevenness of ventilation.

The demonstration of an enlarged physiologic dead space (by determining arterial Pco, and applying the Bohr equation) in such cases would indicate that a ventilation-perfusion ratio inequality exists without elucidating its mecha- nism. It is not permissible to interpret such an enlarged dead space as due to ventilation of unperfused alveoli and hence to postulate a perfusion imbalance, unless the physiologic dead space is very large indeed.

We would, therefore, conclude that there is a large ventilation-perfusion ratio inequality in many cases of apparently pure interstitial dis- ease, that this inequality is dependent almost entirely on uneven ventilation, and that pul-

monary blood flow seems to remain uniform. This interpretation differs from that of Donald and his colleagues. Since the technic used de-

Ventilation-Perfusion Relationships--Read, Williams

pends on sampling expired air, the added possi- bility of true shunts, i.e., perfusion of completely unventilated areas, cannot be excluded.

The cause of the uneven ventilation is not immediately apparent. The degree of non- uniformity is of the same order as that seen in moderately severe emphysema [76]. In emphy- sema, the ventilatory inequality is believed to be largely due to bronchial disease, but the presence of significant airway obstruction was excluded by definition in the present cases of pure inter- stitial disease. It seems that local abnormalities of expansion must account for the inequality in the present series. Certainly it has been shown [79] that the ventilatory inequality in diffuse interstitial pulmonary fibrosis is reversible if the underlying pathologic process responds to corticosteroid therapy.

It might be objected that the present group is weighted by the presence of so many patients with pulmonary asbestosis. The objection may be a valid one. However, the results in patients with asbestosis were indistinguishable from those in subjects with well recognized interstitial disease, and Williams and Hugh-Jones [74] have shown that a functional state of alveolar-capil- lary block is an early and constant feature of pulmonary asbestosis.

In the patients with complicated interstitial disease, blood flow abnormalities were common. It is tempting to suggest that this uneven perfu- sion is due to superadded cysts or generalized emphysema, since one of us has demonstrated [ 761 that perfusion abnormalities are common in emphysema, especially when large cysts are present. However, since these pathologic com- plications are likely to arise in the more advanced and long-standing cases of interstitial disease, the possibility remains that blood flow abnormalities may occur as a later stage in the natural history of the interstitial process itself.

The demonstration of the large ventilatory and ventilation-perfusion ratio inequality in many cases of apparently pure interstitial disease is of some importance. It is possible that the failure to demonstrate ventilatory inequality in a number of series in the past [7,54] is a reflection of the insensitivity of the methods used [20]. Cer- tainly it is demonstrable by a technic of mod- erate sensitivity, e.g., the closed-circuit helium dilution method [8]. The current demonstration that this ventilatory inequality (measured from the argon tracing) may lead to an appreciable ventilation-perfusion imbalance (measured inde-

OCTOBER, 1959

pendently from the oxygen and carbon dioxide tracings) confirms its significance.

The ventilation-perfusion ratio inequality may be of considerable significance in a patient already suffering from a defect of gaseous diffu- sion. If the regions of lung with the highest ventilation-perfusion ratio just produce normal arterial oxygen tensions in end-capillary blood,

then those regions with a lower VA/& ratio will produce low arterial oxygen tensions (and may lead to cyanosis) even in the absence of a state of alveolar-capillary block. In the presence of a generalized diffusion defect at the alveolar- capillary membrane, there is a significant gradi- ent between alveolar and end-capillary oxygen

tensions. Compared with areas of higher VA/& ratio, the alveolar oxygen tension of regions . . with a low v~/Qo ratio is low, and, in addition, there is a greater end-capillary gradient for oxygen in these regions. Hence, the end-capil- lary oxygen tensions of blood from such areas may be reduced considerably below the tensions . . in blood from areas with a higher VA/QC ratio. In an attempt to “adequately” ventilate the

areas of low VA/& ratio, it is necessary for the total ventilation to be markedly increased,

and for the areas of higher VA/QC ratio to be wastefully over-ventilated. Hyperventilation at rest is common in cases of alveolar-capillary block. It is suggested that ventilation-perfusion ratio inequality contributes (with the diffusion defect) to arterial oxygen unsaturation com- monly seen in such patients on exercise, even when hyperventilation prevents it from occur- ring at rest.

The non-homogeneity of “alveolar” gas which results from the ventilation-perfusion inequality obscures the significance of so-called “end-tidal” samples, and hence of end-tidal sampling meth- ods of determining diffusion capacity [S]. The magnitude of the ventilatory inequality is comparable with that seen in many cases of emphysema in which the hazards of end-tidal sampling are rather better appreciated. The single-breath method of determining Dco [77] with its allowance by helium dilution for dis- tributional defects, theoretically offers a better approach to the problem even in these examples of apparently pure diffusion defect.

SUMMARY

Pulmonary ventilation and blood flow rela- tionships have been studied in seventeen subjects

Ventilation-Perfusion Relationships-&xzad, Williams

with apparently pure interstitial disease of the lungs, and in eleven subjects with interstitial disease complicated by cyst formation or proba- ble emphysema.

Subjects with apparently pure interstitial disease frequently had markedly uneven ventila- tion of the lungs which, in the presence of uni- form blood flow, led to marked ventilation- perfusion imbalance.

In subjects with complicated interstitial disease, abnormalities of pulmonary blood flow, not found in those with pure interstitial disease, were common.

Acknowledgment: We gratefully acknowledge the help and advice of Drs. P. Hugh-Jones and J. B. West, and the able technical assistance of Miss H. Macleish.

1.

2.

3.

4.

5.

6.

7.

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