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Journal of
APPLIED
PHYSIOLOGY
VOLUME
DECEMBER
2
1949
NUMBER
in
WARD
S. FOWLER.2
From
the Department
of Physiology
and
Pharmacology,
Graduate
School of Medicine,
University
of Pennsylvania, Philadelphia,
Pennsylvania
V
~~10~s
INVESTIGATORS,
using
fractional
(1-4)
or
continuous
(5)
analysis
of alveolar gas exhaled on a single expiration,
have agreed that the lungs
are not ventilated evenly in normal subjects, i.e. that inspired gas is not evenly
distributed
throughout
the lung gas. The two principal explanations have
been I) that the inspired gas is layered (stratified) in each unit of the lung so
that there is a higher concentration of inspired gas in the alveolar ducts than
unevenly
in the alveolar sacs (I), and 2) that the inspired gas is distributed
to different lobes or lobules of the lungs (2) ; regional differences in ventilation
have been thought to arise because the per cent change in volume varies in
different areas of the lung during inspiration
(4). Roelsen found that patients
with bronchial asthma and pulmonary emphysema showed greater variation
in the composition of successive portions of expired alveolar gas than did
normal subjects; he attributed
this to a greater inequality of intrapulmonary
(2).
gas mixing
Reinvestigation
of this problem has been carried out to obtain quantitative data on this lack of uniformity
of alveolar gas in normal subjects, to learn
more concerning the mechanism by which this is produced, and to devise a
test which might prove of value in the differentiation
of normal intrapulmonary
gas mixing from that occurring in patients with certain types of pulmonary
disease.
The studies to be reported confirm the presence of uneven lung ventilation in normal subjects, apparently on a regional basis. However, they indicate
that preferential distribution
of the dead space gas to certain areas of the
Received
for publication
October
19, 1949.
l This research was supported
by a grant from the Commonwealth
2 National
Institute
of Health
Postdoctorate
Fellow.
283
Fund.
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Ventihtzbn
Lang Faction
Stzcdies, III. Uneven Pdmonary
Normud Szcsjects and in Patients with Pdmondry
Disease1
6
WARD
284
S. FOWLER
Volume
2
lungs may occur regularly and to some extent be responsible for the inequality.
In addition, a ‘uniformity index’ is proposed for the measurement of intrapulmonary gas mixing; this index has been calculated for a group of normal subjects. Although not a direct quantitative measure, it has served to identify
abnormal intrapulmonary gas mixing in patients. Since the test is objective,
requires little cooperation on the part of the patient, and takes only a few
minutes, it may be valuable as a ra.pid screening test for particular types of
pulmonary disease.
METHODS
TABLE
I
.NORMALVARIATIONSINEXPIREDALVEOLARN~CONCENTRATIONAFTERMAXIMALINSPIRATION
OF 02
MEAN
POINTS
zt
S. D.
COMPARED
N2 Difference
Index
Uniformity
%
ah750
-
ah260
ah750
-
ah750
-
1
ah)TC
o-79
2.4
zt
0.5
alvb
5.0
St
1.4
l S. D. and uniformity
indices were
approached
the error of measuremenk
not
calculated,
0.852
0.725
since
the
variations
A
0.040
*
0.066
(0.5
to I. 5%
N2)
gen meter (7), used in these studies, is not sensitive enough to detect accurately
the slight changes in NZ concentration that occur in respired air during the
respiratory cycle, when room air is breathed. However, when the inspired gas,
to be mixed with alveolar gas (80~~ Nz), is not air, but O2 (o.& Nz), the
effect of uneven mixing is magnified so as to be readily detected with this instrument.
Studies were performed with the subjects in the sitting position, except
when noted otherwise. At the beginning of each test, the subject breathed
room air for several minutes through a mouthpiece attached to a J-way valve.
During an expiration, the room air orifice was closed, so that O2was breathed
on the following inspiration and thereafter. In special experiments (table 2),
in addition to the routine measurements of expiratory volume flow, inspired
volumes were measured from a 6-l. recording spirometer used as the source of
Oz. For experiments in which positive expiratory pressure was developed by
expiring against a water column, the flow meter calibration was calculated
from direct spirometric measurement of total expired volume.
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General. The method has been described previously (6). In brief it consists of continuous analysis and photographic recording of I> expiratory volume
flow, and 2) N2 concentration of respired gases during and after the change
from breathing room air to breathing 99.6 per cent Oz. The Lilly-Hervey nitro-
Dectvn ber 1949
UNEVEN
PULMONARY
VENTILATION
285
i
Fig. I. RECORD
OF EXPIRATORY
VOLUME
FLOW (F) and Nz concentration
hyperventilation.
Read left to right. First, expiration
after air breathing,
then maximal
expiration.
For labels under arrows,
see text.
(N) during voluntary
then inspiration
of 02,
uniform throughout
the expiration
and is assumed to be 80 per cent. Then
O2 is inspired. On the next expiration, 20 to IOO ml. of undiluted O2 are expired,
followed by several hundred milliliters of gas with a rapidly rising NZ content,
and finally by gas with a relatively uniform N2 content. The first two phases
represent washing out of the respiratory
dead space, and the last phase, or
plateau, is considered to represent ‘alveolar’ gas. These three phases are not
readily identifiable
in all individuals,
especially those with pulmonary
emphysema. However,
when they are clearly separable (most normal subjects),
the point on the curve representing
the first pure alveolar gas can be located
quickly by the following method.
The point at which the S-shaped curve meets the alveolar plateau is
selected by drawing a straight line on the photographic
record along the top
of the plateau; the N2 concentration
at the point where the plateau line becomes tangent to the rising S-shaped curve is assumed to represent the first
pure alveolar gas (alv,). When expired volume is large, the straight line is
sometimes drawn along only the first half of the plateau, since the NZ curve
in the later part of expiration may change its slope in relation to volume, or
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017
Instrumental.
The characteristics
of the flow meter and NZ meter have
been described previously
(6). Measured points were separated in time by at
least 0.5 second, which is at least 5 times the instrumental
lag. The N2 concentrations
were measured to the nearest 0.5 per cent, corresponding
to about
0.5 mm. change on the record. On the basis of Roelsen’s data (8), we have
assumed that, when the subject is breathing room air, the concentration
of
Nz in alveolar gas after a 65o-ml. expiration is 80 per cent and have calibrated
each record on this basis.
Measurement of Records. The uniformity
index, to be described, compares
the composition of alveolar gas at two different points during the first expiration following inhalation of Oz. The method of selecting these points is consequently a matter of importance for it is essential that both represent alveolar
gas uncontaminated
with dead space gas. Figure I, obtained upon a healthy
adult, shows a typical record and the method of measurement.
During the
first part of the record, air is breathed, the N2 concentration
appears to be
286
WARD
S. FOWLER
Volume
2
the terminal reduction in volume flow may change the slope of Nz increase in
relation to time. The justification
for this procedure follows.
Since we are concerned with alveolar ventilation,
a ventilator-y criterion
is needed to define pure alveolar gas. In terms of ventilation,
alveolar gas is
‘pure’ if it has no admixture of gas from the anatomical dead space. The presence of such admixture can be determined as follows.
During inhalation of OS, the Ns concentration of alveolar gas is progressively reduced on successive breaths. This change in alveolar Nz concentration
can be assumed to be expressed by the equation C,, = Coy%,
For the first several breaths of 02, slight variations resulting from the presence
of Nz (0.4~~) in the inspired gas and the elimination
of blood Nz can be neglected. Thus log C, plotted against PZshould give a straight line, passing through
80 per cent Nz at rto, if the concentrations selected represent pure alveolar gas.
When concentration
points were selected from similar portions of the first
part (02) of successive expired Na curves, Co was obviously zero (0.4~~). When
the Nz concentrations were selected at about the midpoint of the S-shaped
curve, Co was 40 per cent Nz. For Nz concentrations selected at the point at
which the S-shaped curve meets the alveolar plateau, Co was 80 per cent Nz,
and so meet this definition of alveolar gas. The equation is based on certain
assumptions, including constancy of tidal, dead space and functional residual
volumes. These results also apply only to the first several breaths of those
normal individuals whose measured tidal volume was fairly constant, and are
subject to the limits of accuracy of Nz measurement. In some cases Co varied
somewhat from 80 per cent (78.5-81y0), but was the same for various points
on the alveolar plateau; this indicates that early points on the plateau are as
nearly pure alveolar gas as the end-tidal points.
In patients with pulmonary disease and marked unevenness of gas mixing,
alv, usually cannot be selected as above, as can be seen in figure 3. It is necessary that the expired volume preceding alv, be sufficient to wash out completely the anatomical dead space, so that alv, is uncontaminated
with dead
space gas. The wash-out volume has been found in normal subjects to have
an average value of 325 ml. (S.D. + 65 ml.) during quiet breathing (6), or
526 ml. (S.D. + 118 ml.) during maximal inspiration and expiration (see the
section on RESULTS). With maximal lung inflation the dead space and the
volume required to wash it out on expiration are enlarged. Thus, on a patient’s
record an expired volume of 750 ml. is marked on the flow record and the simultaneous point on the Nt record is considered to be alv,; 750 ml. is chosen
because it represents approximately
the mean normal wash-out volume plus
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017
where Co = initial alveolar concentration, about 80 per cent Ns;
c m = alveolar concentration after PZinhalations of 02;
r = alveolar dilution ratio (9).
December 1949
UNEVEN
PULMONARY
VENTILATION
287
SD. This method does not identify the first portion of pure alveolar gas,
but statistically insures that 95 per cent of such points represent alveolar gas
uncontaminated
with anatomical
dead space gas; when alv, is obtained in
this way, it is identified as alv 750. The assumption that the volume required
2
TABLE
2.
EFFECT
OF RESPIRATORY
VARIABLES
ON UNIFORMITY
OFEXPIRED
ALVEOLAR
GAS'
A
TYPE
OF
,SUB
EXPERIMENT
Ja
NO.
OF
ExPTS.
INSP.
VOL.
INSP.
TIME
Total exp.
(maximal
Differences
alvB and
MAX.
EXP.
FLOW
N2
2
3
2
2
Increasing
inspired
vol. normal
pre-inspiratory
lung volume
Varying
inspiratory
breathholding
Varying
expira
tory
time
by
rate
240
sec.
1.6
l/
min.
%
Time
Terminal
exn.
alveolar
vol.
Differences
between alva
and alvb - vol. in col. 2
Unif.
Index
38
37
42
3-S
4-7s
3-S
1940
3020
32.50
4.8
8.0
3
2
2
I
825
830
830
3-O
70
76
76
72
6.5
187s
3-S
4-S
3.6
6.0
0.86
2
2
2
830
3-o
2.8
3.3
0.78
0.87
0.88
900
22.0
980
930
3.3
3.5
S-0
7-S
80
77
4.75
3.0
2.0
8.5
1825
1810
1850
none
89s
87s
87s
added
1350
I 290
350 ml. added
1 All figures
are average
2.5
2.0
I.9
4.5
3.8
1610
2.5
2.2j
1710
1350
3=
74
6.25
3.75
14.50
1440
4-o
2.5
0.66
0.77
20
80
4.2S
I.75
1610
9-I
2.2
0.70
0.86
40
53
38
3.75
61
3-S
4-2s
55
0.80
4.3
4.4
0.89
0.93
1590
S-0
9.75
I-5
---
--
--
--
--
790
74s
760
3.9
3.4
3.7
0.83
0.77
o-53
1430
4-o
4.6
0.84
o-77
1320
3-s
0.81
--
Added
dead space; small
inspira tory lung volume
none added
ISO ml. added
350 ml. added
4.8
s-0
$$kx
-
0.63
0.70
3.75
6s
1940
1940
1940
3.5
2.75
2.1
2.6
4-o
2.5
0.47
0.67
0.78
0.80
0.80
o-79
0.84
770
1950
2450
13.0
3-o
2.7
2.6
3.0
3.5
4-o
2
2
I
950
sec.
840
9.50
9.50
950
0.47
0.67
0.69
0.70
6.5
85s
ml-
3*0
2.7
3.8
5.0
2700
22.0
32.0
%
sec.
840
950
2240
3100
3.9
13.0
Time
-
??‘l.
1720
1-s
Vol.
3-s
4-o
7.25
7-o
34
44
57
62
520
N2
--
values.
to wash out the dead space is not greater in patients than in normar subjects
is supported by experimental data.
Other Ns concentrations,
used for comparison with alv, or alv7ao, may
vary according to the circumstances of the study. One such point can be the
highest NB concentration
on the plateau, found at or very near the end of
expiration;
this is called alvb. The volume of expired gas between alv, and
alvt, can be variable; therefore in a few special studies (table 2)) the points
1
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ml.
Vol.
alv. vol.
exp.)
between
alvb
288
WARD
S. FOWLER
Volume
2
CF-
C i- initial Nfl concentration
C F = final NS concentration
V i= initial volume
Va = added volume of 02.
where
Rearranging,
V
f
=
i
example,
V.
i vi +%va
C
c
c
’c
F. This may be called the ‘dilution
index’. For
F
if one liter (Va) of 02 is added to one liter (Vi) of gas containing
80-40
per cent Nz (c,), cF becomes 40 per cent and ______
=
1.0.
80
If only 600 cc. of
40
O2 is added to one liter of 80 per cent N2 gas, cF becomes 50 per cent
so- 50 =
0.6. In both cases the magnitude of dilution is expressed quantitaso 50
tively by the dilution index. Comparison of dilution in two systems can be
expressed as the ratio of the respective dilution indices, which may be called
the uniformity
0.6
index. Here this is -,
or the added O2 per unit of initial
volume
1.0
in the second case has been only 0.6 of that in the first case. In RESULTS,
dilution
index of late expired gas
In all cases, 80 per
uniformity
index =
dilution index of early expired gas’
cent has been used as the initial concentration.
A uniformity
index can be
computed for any two alveolar concentrations
among those measured (alv,,
alvYGO, etc.). However, for normal subjects, uniformity
indices have not been
calculated for alv, - alvb with quiet breathing, or alv750 - alvlzsO with hyper-
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017
compared were alvb and a point at a measured volume preceding alvb. These
points are designated as alvb minus the volume indicated (e.g. alvb - 1000).
Many patients with cardiopulmonary
disease have a reduced vital capacity an increased residual capacity, and cannot expel as large a fraction of
their total lung capacity as normal subjects. It seemed advisable to have additional measurements on normal subjects which could be used for comparing
similar fractions of the total lung gas. Two such measurements were made for
the normal subjects who made maximal inspirations and expirations. The first
was the NZ concentration
at 125o-ml. expired volume (alv1260) ; most adult
patients can expire 1250 ml. or more in the vital capacity procedure. N2 concentrations were also measured at a total expired volume equal to 50 per cent
of the total lung capacity, estimated from age and vital capacity (IO) ; this
point is called alv3Tc, and was at an average expired volume of 2760 ml.
Cakulation of Results. In any system the dilution of contained Na by added
O2 can be represented by the equation
December
I949
UNEVEN
PULMONARY
VENTILATION
ventilation,
since the differences in NZ concentration
the error of measurement.
were small and approach
RESULTS
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Uniformity
of Expired Alveolar Gas in Normal Subjects. Records were obtained from 45 healthy while males, aged 19 to 38 years, who were breathing
naturally. On the first expiration after O2 inhalation, the expired volume of 5
subjects was insufficient to wash out the dead space and the alveolar plateau
therefore was not evident; measurements were made at alv, and alvb on the
records of 40 subjects. The NZ plateau was approximately
linear in 36 subjects,
was wavy in 3 cases, and in one case showed a sudden step-like rise late in
expiration without coincident change in volume flow. In all, the Nz concentration at alvb was equal to or greater than that at alv,; the average increase was
1.64 per cent with a standard deviation
of ko.84 per cent. Both the slope of
the plateau and volume of expired gas between the measured points were
variable.
Thirty measurements were also made on 18 healthy subjects (6 female,
I 2 male, age I 7 to 73, average 33.7 years) during maximal
expiration following
maximal inspiration
of 02; velocity of breathing was not controlled. These
subjects were semi-reclining,
with the head and trunk elevated 50-60 degrees
above the bed. This position was selected because it is satisfactory for
dyspneic as well as for normal subjects. Average values were: total expired
volume, 4330 ml.; volume to a1v3Tc, 2760 ml.; volume to alv,, 526 ml.; S.D.
AI 18 ml. (all BTPS).
In every case the Nz concentration of the alveolar plateau increased almost linearly with respect to volume throughout most of the
expiration, although during the last several hundred milliliters
it increased
more steeply in some and decreased slightly in others. The results of N2 measurement are given in table I. The uniformity
indices were reproducible; the
S.D. of differences between duplicate measurements (alvT50 - alvb) and their
mean was 0.022 in 12 subjects.
Factors In$uencing Uniformity of Expired A lveolar Gas. The increasing
alveolar NZ concentration later in expiration indicates that inspired O2 is not
evenly distributed
throughout the functional residual gas and also that the
relatively poorly ventilated areas of the lung empty proportionately
more in
late expiration. The following experiments were performed to determine the
effect of varying volume, time and velocity of inspiration and expiration upon
the uniformity of expired alveolar gas.
The best controlled experiments are listed in table 2; column A gives the
differences in y0 N2, volume and time between alv, and alvb; expirations were
always maximal. Comparison of uniformity indices in column A is valid except
for the experiments with increasing inspired volume, in which the uniformity
indices in column B should be used, since the latter have been computed for
290
WARD
S. FOWLER
Volume
2
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equal volumes of gas expired at the same level of lung inflation. In 21 pairs of
duplicate experiments on subject I, the S.D. of the differences between duplicate
uniformity
indices and their means was 0.023, and in the 14 pairs of duplicate
experiments on subject z was 0.024. Thus a difference between the means of
duplicate indices, as listed in table 2, must equal or exceed 0.05 to be significant.
a) Inspiratory variables. It will be noted that as inspired volume increased, the uniformity
of expired alveolar gas increased, i.e. the uniformity
index approached unity (column B), although there was a diminishing
effect
with increasing volumes.
As inspiratory time was prolonged by breathholding
for IO to 30 seconds,
the variation in N2 concentration decreased, but was still 2 to 3 per cent N2
Similar experiments were done by 5
after 20 to 30 seconds of breathholding.
other subjects, comparison being made between uniformity indices of maximal
and b) 20 seconds after inspiration. In
expirations following a) immediately
all, the uniformity
index was greater after breathholding
but did not reach
unity. The mean increase was 0.154, with a significant t value of 4.3. Although
inspired volume was not measured in these 5 subjects, the similarity
of N2
concentrations and total expired volumes in .dicated that it had not varied by
more than IOO to 200 cc. between the comparative experiments; peak expiratory flow was voluntarily
controlled and found similar on measurement. Other
inspiratory
variables were tested without observing any significant effect.
These included rate of inspiratory volume flow (8 experiments, 2 subjects);
preinspiratory
lung volume (12 experiments, 2 subjects); inspiratory flow and
time (8 experiments, 2 subjects) ; and positive (8 cm. H20) inspiratory pressure
(5 tests, 7 control experiments, I subject).
b) Expiratory vareiables. When a maximal
expiration was made evenly,
alveolar N2 concentration increased almost linearly with respect to both time
and expired volume during the major part of the expiration (fig. I). However,
rapid expiration produced a more horizontal plateau than slow expiration
(table 2). Experiments varying the rapidity of expiration were also done by
7 other subjects. With slow expiration the average peak expiratory flow was
34 l/minute,
and with rapid expiration was I 15 l/minute.
In all cases the
uniformity
index (alv, - alvb) was greater with a rapid expiration; the mean
increase was 0.17, with a highly significant t value of 4.6.
When a normal quiet expiration was followed immediately
by a further
forced expiration, as in giving an ‘end-expiratory’
alveolar sample, the N2 concentration no longer increased evenly in respect to volume, but increased rapidly early in the forced expiration, and then remained almost constant during
the rest of the expiration. Such results were found in 6 of 9 normal subjects;
in 3 the slope remained constant despite the interposed forceful expiration.
In one subject, a small increase in uniformity
was found with positive expira-
December
1949
UNEVEN
PULMONARY
VENTILATION
291
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017
tory pressure (IO cm. HzO) ; the mean uniformity
index 0.68 of 7 experiments
was significantly greater than the mean index 0.65 of 7 control experiments.
Cause of Nonuniformity of Expired Alveolar Gas. In addition to the explanations previously offered (‘stratification’
and ‘regional’ concepts) there is
another way in which nonuniformity
could arise, even though the per cent increase in volume during inspiration is equal in all sections of the lung. From
experiments on one normal subject, Rauwerda concluded that certain areas
of the lung fill mainly during the first part of inspiration, and other areas fill
mainly during the latter part of inspiration.
This process we shall call ‘sequential ventilation’.
He also observed that the areas which fill during early
inspiration are less well ventilated than the areas which fill later. On this basis
the following possibility is suggested.
It is certainly reasonable to believe that the dead space gas enters the alveolar spaces first, and the fresh inspired gas (OS in our studies) follows. If
certain areas of the lung fill first, they may receive more of the dead space gas,
while the areas which fill later receive more of the Oz. Then regional differences
in alveolar gas composition will arise toward the end of inspiration even though
the final percentage increase in volume is equal in all areas. This sequential
filling process can be detected by examination
of the expired alveolar gas
only if there is also sequential emptying. The results above show that sequential emptying does occur, with relatively *poorly ventilated areas emptying
preponderantly
later in expiration. If the higher N2 concentration
in these
areas had resulted from preferential distribution
of the dead space (Soy0 Nz)
gas to them, it would be required that the areas which fill first on inspiration
also empty last on expiration.
This concept of sequential ventilation
was tested by studies in which the
sequence of inspired gases was reversed. Inhalations
were made consisting of
several hundred milliters
of 02, followed without interruption
by several
hundred milliters of room air. When such inhalations began at the normal
expiratory position, the usual rising N2 concentration
late in expiration was
found; however, when inspiration
began at an extreme expiratory position,
the slope of the alveolar plateau was reversed. Instead of the usual rising Nz,
now a decreasing N2 concentration later in expiration was found; reversal of
the alveolar Nz slope was obtained in duplicate experiments on 3 normal subjects. This confirms Rauwerda’s results and the ‘first-in, last-out’ possibility.
When the gas that entered first contained 80 per cent N2 (dead space) and
the gas that entered last was 02, a higher N2 concentration was found in the
last expired gas. When the gas that entered first was mainly 02, and the gas
that entered last contained 80 per cent NS, a lower Nz concentration was found
in the last expired gas. This procedure was also used on 5 persons having pulmonary disease (asthma, chronic bronchitis, emphysema). Maximal
inspira-
292
WARD
S. FOWLER
vozums
2
DISCUSSION
In these studies, Nz concentration of expired gas always increased, with
continued expiration, when O2 had been inhaled on the preceding inspiration.
Before this finding can be interpreted validly in terms of alveolar ventilation,
certain points require consideration. The phenomenon does not appear to be
an artefact for the following reasons. a) The increase is much slower than the
instrumental
lag. b) After inhalation of room air, alveolar Nz content is approximately
constant during normal or forced expiration. c) After breathing
O2 for several minutes and then inhaling one breath of room air, the expired
alveolar gas regularly shows a decreasing NZ content later in expiration. d)
After a large inspiration of 02, the N2 concentration
of 3000 ml. of expired
alveolar gas may rise by 7 per cent; this would represent an addition of at
least 105 ml. of N2 or 133 ml. of air, which is too large to have come from pulmonary venous blood, lung tissue or the oronasal cavities, or to be attributed to
an R.Q. effect.
The increasing NI content cannot represent a decreasing amount of admixture with O2 from the respiratory dead space, ‘pure’ alveolar gas being
expelled only at the extreme end of expiration, as Armitage and Arnott suggest
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tions and expirations were made (average 1790 ml.) ; inspired gas was either
all 02, or the first half was O2 followed without interruption
by room air.
After inhalation of O2 alone, the plateaus showed considerable upward slope.
However, after the Oz.-air inhalations, the plateaus in every case were more
nearly horizontal. Uniformity
indices, calculated from NZ concentrations at
750 ml. and end-expiration,
were, with Os-air inhalations, increased an average
of 0.196, with a highly significant t value of 7.8. These changes are of course
similar in direction to those in normal subjects.
If variations in the composition of alveolar gas were due solely to sequential filling, the volume of the dead space should limit the extent of variation,
and greater variation would be expected when the dead space was increased.
Experiments on 2 normal subjects were made in which dead space was added
by interposing air-filled rubber tubing between the ,+-way valve and the source
of Oz. When inspiration began at the normal expiratory level, the addition of
150
or 350 ml. of dead space did not affect the uniformity
of expired alveolar
gas; however, when inspiration
began at a deep expiratory position, more
variation in composition was found with added dead space (table 2). Eight
subjects with chronic pulmonary disease made vital capacity inspirations and
expirations (average 2580 ml.); inspired gas was, in each subject, either all
02, or 650 ml. dead space was added. Comparison of uniformity indices, calculated from NZ concentrations at 750 ml. and end-expiration,
showed them to
be smaller in all cases with added dead space. The mean decrease, 0.06, was
highly significant, having a t value of 4.9.
Decem her Ig4g
UNEVEN
PULMONARY
VENTILATION
293
(I I), for reasons discussed under the section on METHODS.
Furthermore,
the
addition of more than 400 ml. of O2 would be required, during a sooo-ml.
expiration, to depress the plateau concentrations an average of 3.5 per cent
N2 below that of the pure alveolar gas, represented by alvb. This volume, 400
ml., added to the 150 to 200 ml. of O2 expired prior to the plateau, is much
greater than the volume of the respiratory dead space.
Thus, one may conclude that the plateau represents alveolar gas and that
the variations in expired alveolar Nz concentrations,
by exclusion, must be
TABLE
BEFORE
INSPIRATION
Lower
area
lung
360 80
720
l See figure
80
AFTER
INSPIRATION
2
MECHANISM
DS
--
02
upper
lower
40
320
80
640
upper
lower
40
80
320
0”
2
n
Expansion
20 340
LOO 1700
upper
lower
r20
240
720
N2
ml
%
360
720
varies
varies
Uneven
ventilation
due to stratification
44-4
44*4
Even ventilation
with
uneven expansion
360
1800
42.2
26.0
Uneven
ventilation
due to different
yO
vol. change
360
720
53.3
40.0
Uneven
ventilation
due to preferential
distribution
of dead
space gas
640
upper
lower
0
MECHANISMS~
and text.
attributed principally
to unequal distribution
of 02 throughout the functional
residual gas.
These studies confirm previous findings that the lungs are unevenly
ventilated in most healthy subjects, even during a maximal inspiration. The
average uniformity index, 0.725, is similar to the magnitude of variation in composition of expired alveolar gas reported by Roelsen and Mundt. However,
the observed variations in Nz concentration during an expiration represent only
the minimal variations which could have existed in the lungs at end-inspiration. For example, marked regional differences could exist in the composition
of alveolar gas, but go unnoticed if the proportion of gas delivered to the expired gas from each region remained constant throughout expiration. Since
the Na concentration does increase later in expiration, the proportion must be
changing progressively in favor of poorly ventilated areas. However, the change
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lung
Vol.
added
N2 No.
space
Upper
area
OF VENTILATION
INSPIRATION
Vol.
Dead
3. ILLUSTRATION
WARD
294
Volume
S. FOWLER
2
in proportion,
or the relationship between the emptying of various areas can
be altered. The sudden increase in NZ concentration with an interposed forceful
expiration indicates that emptying of poorly ventilated areas is promoted to
a greater degree than that of well ventilated areas. When the total expiration
is more rapid, the increased gas uniformity
suggests that poorly ventilated
areas are emptied early in expiration to a greater extent than when expiration
is quiet. Mundt’s failure to note the effect of changes in expiratory rate may
have been due to the use of Hz, or to comparing only the differences in the last
liter of a maximal expiration. The slope of Nz increase in the last liter is not
always equal to that in alveolar gas expired earlier and may not show changes
which are evident in the total expired alveolar gas; with this Rauwerda agrees.
Open and closed
circles
represent
N2 molecules.
Central
figure shows pre-inspiratory
conditions in 2 lung areas and dead
space. Figs. 14 correspond
to
conditions
in table 3, after inspiration
of a Nz-free
gas (02).
See text.
3
4
If analysis of the expired gas is used to determine whether end-inspiratory
variations in alveolar gas composition
can be changed, expiration must be
controlled. Although the expiratory flow pattern is obviously an incomplete
registration of the emptying process, similarity of flow patterns is at least some
indication of a similar emptying process, and appears to be one of the requirements for reproducing the alveolar plateau. With such control, it appears that
larger inspired volumes promote equality of alveolar ventilation.
This is compatible with either of the theories of unequal ventilation.
There are two main theories concerning the mechanism of uneven ventilation. The first states that the inspired gas is layered or stratified in each individual air unit throughout the lung so that there is a higher percentage of inspired gas in each duct and atrium than in the slightly more peripheral alveolar
sacs; this might give rise to a progressive increase in Nz concentration throughout expiration
(table 3, fig. 2, mechanism I.) However, Rauwerda believes
this theory to be untenable, since his calculations showed that, within one
second, diffusion would obliterate
any differences existing within the unit
consisting of an alveolar duct and its alveolar sacs. He showed that during 15
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2. VARIOUS MECHAOF PULMONARY
VENTILA-
Fig.
NISMS
TION.
December
1949
UNEVEN
PULMONARY
VENTILATION
295
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017
to 30 seconds of breathholding
after O2 inhalation,
the differences in alveolar
gas concentrations are reduced, but not eliminated;
our results using similar
periods of breathholding
confirm this with respect to N2. He concludes that
differences which disappear have done so by diffusion inside individual lobules
or between adjacent lobules; the differences which do not disappear represent
variations in the composition of gas in more widely separated areas of the lung.
The second, and more likely, concept is that regional differences exist,
namely that inspired gas is distributed unevenly to different lobes or lobules
of the lung. In 1909 Keith (12) pointed out that the expansion of various parts
of the lung may be unequal, since the lung is composed of elements of varying
degrees of distensibility.
The root zone, containing large bronchi and vessels
and much fibrous tissue, offers greater resistance to a distending force than the
peripheral subpleural zone. It must be remembered, however, that unequal
expansion will produce unequal ventilation
in different regions only when the
percentage increase in volume varies in the different areas of the lung. In that
case, non-uniformity
of alveolar gas would occur (2, 4). These mechanisms are
illustrated in figure 2, mechanismsz and 3.
There is also another way in which regional diff erences in composition could
arise, even though the percentage increase in volume was equal in all sections
of the lung (fig. 2, mechanism 4). This results from sequential ventilation,
which indicates that certain areas of the lung fill before, and empty after, other
areas. When sequential filling occurs early in inspiration, the first gas entering
the alveolar spaces (dead space gas) is distributed preferentially to those regions
which expand first. Experimental
evidence has been obtained which supports
this mechanism as being a cause of uneven alveolar ventilation in both normal
subjects and in patients with pulmonary disease. However, such evidence was
obtained in normal subjects only when inspiration
began at an extreme expiratory position, but not at the normal expiratory position. The cause of this
difference is not apparent. The regional intrathoracic
distribution
of various
forces interacting to cause gas flow in and out of the lungs is not well understood, either with respect to magnitude, time course, or variation at different
levels of lung inflation.
If variations in alveolar gas composition were due solely to inequality in
the percentage increase in volume, it is not apparent why the variations should
be affected by changing either the sequence of inspired gases or the volume of
the dead space. It is possible that both mechanisms, unequal percentage changes
in volume and sequential ventilation, occur. The uniformity of the composition
of alveolar gas would then depend on the relative magnitude and spatial distribution of the two processes.
When breathing air, the O2 content of alveolar gas depends on both the
loss to the pulmonary
blood (perfusion) and the gain from the inspired air
(ventilation).
Although the results above measure only the ventilation
factor,
296
WARD
Volume
S. FOWLER
2
they suggest some of the variables which may be involved in obtaining reproducible Haldane-Priestley
alveolar samples, a procedure which is well
known to require considerable training. The marked variation present in a
single alveolar expiration emphasizes that a single small sample of alveolar
gas may not be representative of the total expired alveolar gas. Rahn and associates (13) found concentrationsof 02 in alveolar gas to decrease in order when
samples were obtained 1) at the end of normal tidal volume, z) at the end of
forced expiration begun at end-inspiration,
and 3) at the end of forced expiration begun at end-expiration.
The differences were attributed to the time required for the forced expiration. The significance of the differences between
various types of alveolar gas samples is currently debatable. Barker et aZ.
(14) found the pCOz to be lower in the end-tidal samples than in arterial blood,
3. RECORDS
OF
EX-
(F) and
N2 concentration
(IV) during voluntary
hyperventilation.
First,
expiration
after
air breathing,
then
(1-2)
inspiration
of 02,
then expiration.
N:! concentration at alv1250 exceeds alvvao in the
normal
record
by I per cent,
in the emphysema
record
by
9 per cent.
VOLUME
FLOW
and Forssander and White (IS) believe that end-tidal samples are diluted with
air from the dead space. However, Rahn (16) found close agreement between
end-tidal and arterial tensions. The present studies indicate that end-tidal gas
comes chiefly from well-ventilated
alveoli. As Roelsen pointed out (8), alveolar
gas samples at the end of a deep expiration come from relatively poorly ventilated alveoli. In such a terminal sample of expired gas, gas from poorly ventilated alveoli will be represented to a greater extent a) when the total expiraHaldane-Priestley
samples than in
tion is slower, and b) in end-expiratory
end-inspiratory
samples. The latter is because the normal tidal expiration
empties mainly well ventilated alveoli; this gas is not available for admixture
in the end-expiratory
sample.
The experimental procedure used in the study of normal subjects has been
extended to an investigation of patients suspected of having abnormal alveolar
ventilation.
The patient is asked to make a maximal inspiration of 02 and
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Fig.
PIRATORY
December
1949
UNEVEN
PULMONARY
VENTILATION
297
SUMMARY
Continuous analyses were made of Nz concentration and volume flow of
gas expired after one inspiration of 99.6 per cent Oz. A ventilatory criterion for
identifying alveolar gas is given. After 02 inhalation, the Nz concentration of
Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017
follow this by a maximal expiration (vital capacity procedure).
Nz concentrations are measured at alv 7Go,alv1250, and at alvb. Our studies confirm Roelsen’s
finding that patients with bronchial asthma and pulmonary
emphysema show
much greater variation
in the composition
of alveolar gas than do normal
subjects (fig. 3). In normal subjects, the difference between a1v1260and a1vT60
is not more than 2 per cent N2; this may increase to 3 to 4 per cent in patients
with uncomplicated
bronchial asthma and to IO per cent in patients with
marked pulmonary
emphysema.
For reasons noted previously
in the section
on METHODS, these differences have not been expressed as uniformity indices.
However in the range of Nz concentrations usually found, 20 to 50 per cent,
the relationship between percentage N2 differences and uniformity indices is
such that larger percentage Nz differences correspond roughly to smaller uniformity indices. The normal uniformity index, calculated for alvTboand alvb is
0.725 (SD. =t 0.066), and may decrease to 0.50 in some patients with asthma
and to 0.25 in patients with severe emphysema. If the total lung capacity has
been measured, the uniformity index calculated for alvTsoand alv*rc is useful,
particularly in patients having slightly abnormal plateaus. Such patients may
expel only 50 to 60 per cent of the total capacity and the uniformity index
(alv760
- alvb) may be 0.65 to 0.75. Such values are compared better with the
normal index for alv750 - alvfTC, which is 0.852 (SD. ~fi 0.04) than with
the normal index for alvT50 - alvb (0.725 =t 0.066), which represents expulsion
of about 80 per cent of total capacity. Detailed data upon patients will be presented elsewhere.
Findings in patients such as these were attributed by Roelsen to increased
variation of alveolar ventilation. However, variations in the composition of
expired alveolar gas depend not only on uneven ventilation but also on the
relations between the emptying of different areas of the lung. Thus the differences might not be solely the result of greater variations in alveolar ventilation,
but be entirely or partially due to different emptying patterns; qualitatively,
this is unlikely, since other evidence (9, 17) indicates the presence of abnormal
ventilation in emphysema. However, at present this limits the validity of using
the variations in compositions of expired alveolar gas as a quantitative measure
of the uniformity of alveolar ventilation. Despite this, such measurements
are useful clinically. With the continuous analysis method, they can be made
rapidly and with a minimum of subject cooperation, and may be useful as a
screening test for patients suspected of having abnormal pulmonary gas
mixing.
298
WARD
S. FOWLER
Volume
2
The author wishes to thank Dr. J. H. Comroe, Jr., and Dr. S. S. Rety for valuable
advice.
REFERENCES
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2.
3.
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alveolar gas increased as expiration continued. During maximal ventilation
the average increase in alveolar Na concentration
was 5 per cent; the uniformity index was 0.725, which expresses the minimal variation in dilution of
alveolar NB by inspired Oz. This finding indicates a) that inspired O2 is not
evenly distributed throughout the functional residual gas, and b) that the relatively poorly ventilated areas of the lung empty predominantly
later in expiration. Uniform end-inspiratory
distribution
of inhaled O2 is favored by
larger inspired volumes and by breathholding.
Uniformity
of expired alveolar
gas is affected by the rate and manner of expiration.
The interpretation
of
data utilizing single alveolar gas samples is discussed.
Experimental
evidence was obtained against the stratification
theory of
uneven lung ventilation and favoring the regional concept. A new concept, with
supporting evidence, has been advanced to explain uneven ventilation
on a
temporal basis; this sequential ventilation results in a preferential distribution
of the respiratory dead space gas to those regions which fill first on inspiration.
Both preferential
distribution
of the dead space gas and also variations in
percentage volume changes may occur as explanations for uneven alveolar
ventilation.
Subjects with bronchial asthma and pulmonary
emphysema showed
greater variations in alveolar gas composition than did normal subjects. This
difference makes the test useful in clinical diagnosis; measurements are made
easily and rapidly. Their present limitations
as a quantitative
measure of
intrapulmonary
gas mixing are noted.
December 1949
UNEVEN
PULMONARY
12. HILL, L. F&her Advances iut Physiotogy. New
p. 182.
A. B. OTIS AND W. 0.
13. RAEXN, H., J. MOHNEY,
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E. S., R. G. PONTIUS, D. M. AVIADO,
Proc. 8: 7, 1949.
15. FORSSANDER,
C. A. AND C. WHITE. J. Applied
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