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STUDIES IN MAN OF THE VOLUM\1E OF THE RESPIRATORY
DEAD SPACE AND THE COMPOSITION OF THE
ALVEOLAR GAS'
BxY
A. P.
FISHNMAN
'
(Prom thc DePartnctia of Medicine, Cohinmbia UnivcrsitV, C olleyc of PIhlysicians and Snirgeons,
aid the Cardio-Plmdnonary Laboratory of the First lledical and Checst Serviccs
(ColnmbZllia Un1iversity Divisioni), Bellezivc Hospital, Ncwc, York, N. V'.)
Stubmiiitte(d for puiblication July 14, 1953; accel)ted \November 18, 1953)
The expired breath may be consid-lered to derive
from tw o sources: 1. A respiratory dead space,
where inspired gas (corrected to BTPS) has not
exchainged oxygen and carbon dioxide with the
blood and thus retains its identity; andl 2. an alveolar space, which contains inspired gas modified
by exchanges of oxygen and carbon dioxide (at
BTP'S) with blood. The volume and composition
of this alveolar component of the expired breath is
(letermiineid by the respective volumes of the total
ventilation andl of the respiratory dead space, and
l)y the relative contributions and ventilation-perfusion ratios of the gas exchanging areas of the
Interest is currently focussed on the analysis of
the factors influencing the exchange of oxygen and
carbon dioxide between the blo)10 an(l gas phases
of the lung under a variety of experimental conditions. To this end, respirator)' equations have
been developed which inclutde as unkinowins either
the volume of the respiratory dead space or the
composition of alveolar gas. A new indirect
method for determination of these two essential
factors has been recently described by Pappenheimer, Fishman, and Borrero (1) and studied in
anesthetized dogs and also in a few normal subjects. This method, hereafter referred to as the
"iso-saturation method." makes possible the
graphic solution of the Bohr formiiula for both the
volume of the respiratory deadl space and for the
composition of alveolar gas; it entails the mleasurement of the composition of expired air over a
wide range of tidal volumes, while respiratory gas
tensions in the blood leaving the lungs are maintained constant during controlled hypoxemia.
The purpose of this paper is to extend the observations made on normal man with the iso-saturation method, and to explore its applicability to
subjects with abnormal pulmonary functioni.
lungs.
These considerations are the basis for the Bohr
formultla:
- PA) VT
(P
VI)~ = =
(P.VTA)
1
(I)
where
VT = tidal volunme
volume containing respiratory (lead space
NrD
gas
VAx volume containing alveolar gas = VT - VD,
PItx PAX. PEx = the partial presstures of the gas in
inspired, alveolar and expired gas, respectively; all volutmes are expressed at
body temiiperature, pressure, saturated
with water vapor (BTPS),
Principle of thc "Iso-Saturation MeIothod"
In order to facilitate the presentation of the results, the method, previously described in detail
by Pappenheimer, Fishman, and Borrero (1). is
l)riefly reviewed.
and by substitution and rearrangemiient, UsiIng oxy<gen (0,2) as the test gas A-
1 This investigationi -as sul)l)orted (in l)art) by a research grant (PHS Grant H-833 (C)) from the National Heart Institute of the National Institutes of Health,
Public Health Service, with additional support from the
Life Insurance Medical Research Fund and the American
Heart Association.
2 Established Investigator of the Americatn Heart
Association.
VDO,
VT
PEO.,
PIo,
-
PAo,
-
PAo.,
(2)
If the alveolar., as well as the inspired, gas mixture could be maintained constant despite variation in tidal volumne, equation (2) then 'would be-
469
.470
A. P. FISHMAN
come (1, 2)
VDo2 - K-PEo, - K1
VT
(3)
where,
KP
Plo,
and K1 = K PAo2.
PAo,
Similar considerations apply to the use of carbon
dioxide (CO9) as gas x.
The respiratory dead space. It is apparent
that in equation (3), the volume of the dead space
has become a function of the tidal volume and expired gas composition. It was indicated in the
original report (1) that graphic solution of the
Bohr formula with constant inspired and alveolar
gas permitted evaluation of two experimental
possibilities:
1. VDO9 varies proportionally as VT SO that
VT2 is constant and . . PEO2 remains constant as
VT varies.
2. VD02 is constant and independent of VT, SO
that PEO9 varies linearly as V
The two possibilities are illustrated in Figure 1A.
These possibilities were experimentally tested in
the previous study (1) and it was shown, under
the conditions of the experiments, that VD02 =
K. Consequently, progressive decrease in tidal
volume until VT = VD. (where x is either oxygen
or carbon dioxide) makes PE. = Pi., and numerical values for VDX may be obtained by extrapolation. This is illustrated for VD02 in Figure 1B,
and compared with VDCO2 in Figure 1D.
1 =
Alveolar gas tension. When V
VT 0, PA,
PEX and a numerical solution for PA. can be obtained by extrapolation. Figure 1C illustrates the
use of this method to obtain PAO2 and Figure 1D
includes the determination of PACO02
The application of the iso-saturation method to
the solution of equation (3) depends on the use
of arterial blood as an index to constant mean
alveolar gas composition. Earlier experiments
(1) with inspired gas mixtures low in oxygen
content, have demonstrated that with controlled
respiratory frequency and over a wide range of
tidal volume, a stable degree of arterial hypoxemia
* ~~~~~~VDO2
0
=
so
K
60
V
T02
..
-I
o
VDO2:K
a
*A
0
~
Plo2
.__j
so
0
a. 6 0
K
WHEN PEO2: PIo2 , VO02- VT
BOHR FORMULA WITH Pl02 AND PA6p CONSTANT
40
40
..001
.002
YVT
A
Plot0 -'.+
.001
.004
.003
a
.002
a
,'
.0 03
.005
.004
I,
YVT
B
-
..
40
WHEN VT O0,
so
PECOg:- PACOg
0
0
*PACOF
0.2
40
I~0
WHEN /VT= 0. Pco2
.001
.
.002
a
=
.003
I
L
PAO2
.n
O *
.004
a
WHEN
.002.
.001
*
.003
.O04.
..
a;
D
.005
t
PICo2 °O.VDCo-2VT
YVT
I,
'VT
C
FIG. 1.
GRAPHIC SOLUTION OF THE BOHR FORMULA
FOR THE
DETERMINATION
OF
VDO2, VDCO2., PAO2, PACO2 (SEE TEXT)
4711
RESPIRATORY DEAD SPACE AND ALVEOLAR GAS COMPOSITION
be achieved, employing an oximeter as a nullpoint indicator of arterial per cent HbO2 saturation.
Furthermore, under these conditions, the linear
alignment of the experimental points relating the
composition of expired air to the reciprocal of the
tidal volume, implies constancy of mean alveolar
gas composition, and, therefore, of the A-a
gradient.
can
METHODS
All experiments were done with the subject comfortably
seated. In each experiment, successive points were obtained, at different respiratory frequencies. Frequency of
respiration ranged from 8 to 88 per minute and was fixed
for each experimental point by synchronization of breathing with a metronome; the depth of ventilation was regulated voluntarily so to maintain a constant per cent HbO2
in arterial blood as controlled by oximetry, thus insuring minimal fluctuations in Pao2.
In some instances, a mild degree
of exercise was used
in order to achieve larger tidal volumes. This was done
by means of a stationary bicycle ergometer, allowing
sufficient time (approximately 15 minutes) for a steady
state of respiration and of circulation to be reached.
A Millikan oximeter (single channel with compensated circuit, C.M.R. Model 13) was used throughout
these experiments as a nullpoint instrument. This device
permitted the subject to adjust his ventilation so as to
return to the same per cent HbO2 mark on the galvanometer dial during successive experiments. The exact saturation corresponding to this mark was determined by arterial blood sampling and determination of its oxygen content and oxygen capacity with the Van Slyke-Neill apparatus.
In subjects free of pulmonary disease the oximeter
scale was set at 100 after approximately 5 minutes of
breathing 100 per cent oxygen, whereas in patients with
pulmonary disease, the per cent HbO2 in arterial blood was
determined directly by gas analysis, and the oximeter
scale set accordingly. The instrument was checked for
drift or instability at the end of each determination, and a
deviation of greater than 2 per cent from the initial "ear
thickness" or "saturation" readings caused the experiment
to be discarded. An appropriate inspired mixture of oxygen in nitrogen was chosen in order to reduce the per
cent HbO2 saturation in arterial blood to a range of 70 to
80 per cent. Whereas a 10 to 12 per cent oxygen mixture
was needed to accomplish this comfortably in normal subjects, higher inspired oxygen mixtures were required in
one of the subjects with pulmonary disease. The inspired
mixture was made available through a demand valve as
the subject breathed in time with a metronome, adjusting
his tidal volume to reach the indicated saturation. Approximately 10 to 15 minutes after stabilization at the
indicated galvanometer reading, three washouts of the
spirometer with expired gas were completed, and a twominute sample was collected for measurement of tidal
volume and analysis. Repeated measurements of ventila-
tion, oxygen intake, and respiratory exchange ratio obtained between 10 to 15 minutes after stabilization of the
galvanometer reading, suggested that a steady state of
ventilation, circulation, and gas exchange had been
reached.
Arterial blood samples were drawn during the gas collection period through an indwelling brachial arterial
needle, previously placed following novocaine anesthesia.
Pao2 and Paco2 were determined directly and indirectly,
in duplicate, according to methods previously described
(3, 4). The results by both methods were required to
check within 2 mm. Hg, for inclusion in the study. The
partial pressures of oxygen and carbon dioxide in expired and inspired gases were calculated from the results
of gas analysis using the 0.5 ml. micro-Scholander analyzer. With data thus obtained, the A-a gradients and
oxygen diffusing capacity (DLO2) of the lungs were calculated. For the latter calculation, made only in normal
subjects, (a) the oxygen uptake figure was the average of
multiple measurements; (b) the meani oxygen pressure
gradient between the alveolar gas and the capillary blood
was determined by a modification of Bohr's graphic integration method previously described (5), assuming that
the mixed venous-capillary blood per cent HbO. difference
was 25 per cent and that, at the level of hypoxia employed, the venous admixture component of the A-a gradient was negligible. Obviously these assumptions can only
apply to the normal subject.
Subjects for study
Eight normal subjects and three patients with abnormal
pulmonary function were investigated. The pertinent
vital statistics appear in Table I. The three patients selected had not on previous studies shown significant
physiologic variation from day to day. They represent
three distinct types of pulmonary dysfunction: 1. Nonobstructive emphysema; 2. overdistension of a normal
lung following pneumonectomy; and 3. alveolar-capillary
TABLE I
Vital statistics of eleven subjects studied
Body
Stubject
Age tSex Height
cm.
area
Vital
capacity
m2
ml.
surface
2.08
2.20
1.99
1.84
2.05
1.63
2.00
1.90
A. P. F.
P. S.
W. B.
S. R.
M. B.
L. D.
G. J.
R. Mc.
G. W.
33
30
32
38
29
28
36
30
67
m
m
m
180
168
182
175
169
G. B.
49 m
180
1.84
E. H.
19 m
175
1.68
m
m
m
m
m
f
183
185
180
174
1.70
I)iagnosis
5130 Normal
4740 Normal
5560 Normal
4450 Normal
5400 Normal
4300 Normal
6560 Normal
4860 Normal
3040 Non-obstructive
pulmonary
emphysema
2315 1 month post right
pneumonectomy
2860
Diffusepulmonary
granulomatosis
A. P. FISHMAN
472
are necessary to define the volume of the respiratory dead space (VDO2 and VDCO2) and the alveowith various types of pulmonary insufficiency
lar gas composition (PAO2) and (PAC02)
The points obtained during mild exercise in two
Normal G. W-. G. B. F. H.
Meastirement
ects are indicated by separate symbols in the
subj
Lung volumes in per cent
figures an(l fall on the samle straight line as those
of predicted value
5
experiments performed
105*
obtained attrs.I
rest. In a few
73
100
Vital capacity
etre
otie
eveprnet
61
100
113
104*
Total capacity
83
145*
100 254
during miore strentious exercise, the points fell
Residual air
the line. They w-ere invariabhlv associated
above
Residual air X 100
25
27
33
55
wsith a higher respiratory exchanige ratio ( RE) than
Total capacity
recordled in Taable III. Sinlce either a change in
Maximum breathinig
A-a
gradienit or failure to achieve the steady state,
in
cent
capacity per
42
100
of predicted value
miay account for these observations, and since a
100 71
fixed A-a gradient and maintenance of a steady
Alveolar N2 per cent
after 7 min. pure
25 2.17 1.08 1.58 state are p)rerequisite for the application of the
oxygen breathing
2 .ethod, these few points are niot illutstrated in the
Ventilation in L./min./
figures.
TABLE II
Summary of physiologic measurements in the three patients
sq.m.b.s.t
Rest
1 min. standard exercis;e
Arterial blood "'/ HbO2t
Rest
1 min. recovery, postexercise
Arterial blood
Carbon dioxide pressurre,
at rest, in mm. Hg$
*
Compared
to
3.1
10.7
5.46
12.10
96
95
96
95
38
42
6.50
19.70
96
predicted values for niormal
92
75
lun1g.
t Sq.m.b.s. = square meter of body surface area.
t While breathing 21 per cent oxygen.
block associated with diffuse granulomatosis of the lunlg.
The results of pulmonary function studies on) each of the
three patients are presented in Table II.
RESULTS
The results in the eight normal subj ects and in
the three patients will be considered separately.
All measurements made at rest and data calculate(d
therefrom, are summarized in Table III, including
the volume of the respiratory dead space and the
composition of alveolar gas obtained by, extrapolation.
Normal Subjects
The results confirm those previouslyr reported
(1) and are illustrated for two subj ects in Figures
2, 3, and 4. These figures are representative of
those obtained in all the subjects, and demonstrate
that the experimental points cluster around a sloping straight line with a minimum of scatter, and
therefore make possible the extrapolations which
T 'olut1l *JOf t/Ic r tS/iraltoV (d(cd1 SP(cc
The miiaini tfinidinigs concerning the volutnicm1 of the
respiratory, dead space wAere as follows: (a) The
sloping straight line inidicates (equiatioin (3), Fi
tires 1 and 2), that \TV is constaint dlespite variation
in VT; (b) the addition of a mneasured external
dead space increases the calculated VD by ani
amount equivalent to the w-ater capacity of the
added tube. As seeni in Figtire 4, Do., an(l
\VDco., increase by 156 ml., and 150 ml., respectively, after addition of an external VD of 150 ml.
A:s seen in the same figure, the application of a tight
abdominal binder to change the midposition of the
clhest, did not alter significanitly eithier the VDO., or
the VDCO.,; similar observations w-ere imiade in suibject P. S.; (c) the VD is fixed and is iiot influenced
Ibv variationis in the compositioin of the loNw oxygen
mixture wNhich is ise(l to miiaintaini iso-saturationi
(Figure 3); w-hen the same type of experiments
are done 1w) a trained subject, wNitholut anoxia or
oximneter conitrol, tising room-i air as the inspired gas
mixture, and voluntary adjustment of tidal volume
to achieve cotmfortable ventilation at a given frequency, a considerable scatter of experimental
points is observed (Figure 5). This scatter was
anticipated since the subject maintained his arterial per cent HbO., in the upper, flat, part of the
oxyhemoglobin dissociation curve, where slight
changes in per cent HbO.. may be associated with
marked changes in Pao.,; (e) during all the experimental variations described above, VDO., and
VDCO.. remained approximately equal.
473
RESPIRATORY DEAD SPACE AND ALVEOLAR GAS COMPOSITION
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474
A. P. FISHMAN
SPACE FOR OXYGEN (Vo0o)
DETERMINATION OF DEAD
AND
ALVEOLAR
PARTIAL
OXYGEN
(PA.0)
HbO2: 80tz2 S
OXIMETER,
SUBJECT: P.S.
PRESSURE
uLJ/Mm. STPD )
(Vo2, 275 35
X-LIGHT EXERCISE (V02 560- 690 ML.MIN.STPD)
0-REST
80
PiO,
so
INSPIRED
-
Fio2 (PB 47) = 78.5 MM.HG.
OXYGEN
0-:A
PRESSURE
PARTIAL
VDo0, 2 4 1NL.
701-
INCLUDING 75 ML.
EXTERNAL DEAD SPACE
Id
Wya
60
.
-0
w00
>
{..w
_
x e
-
-
-
_
_
_
_
-THEORETICAL
_
L
_ _
_
_
_
_
FOR
THEORETICAL LINE FOR
I
o 9L
a.
VD20.25 VT
50
X 44
40
.001
i
0ooo
'500
.0,05
.004
.003
i
333
.002
i
i
YiT
i
200 VTSTPS
.5o
A
DETERMINATION OF DEAD
SPACE FOR
CARBON DIOXIDE (VoDco)
AND
ALVEOLAR
CARBON DIOXIDE
SUBJECT: PoS.
mu
He
w
a
x *
0 '
o
Z *
S.
I
Li
PAcopz3 I
OXINETER
PARTIAL
PRESSURE
(PAGO.)
HbO2 a 80±2 %
mm. He.
z
o,
a:
~IL
:9 _
c
e.-
IL a
X 44
201
0
a.Qd
VDo,
a.
246ML.
INCLUDINGN 75 ML.
EXTERNAL DEAD SPACE
10
- I001
i
1000
002
-
.003
-aw
o00
333
.0oo9
a 5T
-IN;P0o
9
200
VT 9tPs
B
FIGS. 2 A AND B. ILLUSTRATIONS OF THE APPLICATION OF THE ISO-SATURATION METHOD
Note that the experimental points fall
on a sloping
straight line.
A
NoRxAL SUTBzcr
475
RESPIRATORY DEAD SPACE AND ALVEOLAR GAS COMPOSITION
un
nX
8 5 MN."G.
PIOn:
-&
I
- -
-.S ,, '
so
VDOP_ 238 ML.
O
Pt02: 74NM.HO.
vot
4
0*
0
- 70
0.
wo
~
la
~
.01
0
~
00:36L
Ni
0.
_
,
0,/
_
-
__-
50
I
SUBJECT: A.P. P.
Not:47mm. HG.
Fiop.l
401
PACO2:33 MU. He.
30
0
0.
I.-
vAO
Fiop
EFFECT OF VARYING
AT CONSTANT
SATURATION - 8 0. %
OXIMETER
1 8 AND
.103
X=REST AND LIGHT
EXERCISE
*=REST AND LIGHT
EXERCISE ,
_v
Hbop2
,
F102 :1 1 8
Ftop=
.103
* INCLUDING APPARATUS DEAD SPACE OF 75 ML.
20
a0
PACOp228MM. HG.
0
a
hL I
_ _e
Ab
)3 _% _
00
-
0
1000
i
.o00
500
333
.002
.003
-i-
VDCO2 : 236
OF THE
Alveolar gas composition
The extrapolated values of PAO2 and PACO2 obtained under the conditions of these experiments
ranged, respectively, from 42 to 55 mm. Hg, and
from 26 to 33 mm. Hg. These variations are in
part related to the different degrees of hyperventilation required to maintain approximately the
same level of per cent HbO2 saturation. This effect is well illustrated in Figure 3, where two different inspired gas mixtures were used to maintain
the same per cent HbO2. It can also be seen in
Table III, that the exchange ratio of alveolar gas
(RA) obtained by extrapolation corresponds
closely to the expired gas exchange ratio (RE).
200
N.
-..005
.004
ISO-SATURATION METHOD IN A NORMAL SUBJECT-EFFECT
GAS MIXTURE
Note that VD%o and VDCO2 remain constant and equal, and that PAo% and PACO, vary.
FIG. 3. APPLICATION
ML.
OF
VTBTPS
a
/VT
I
VARYING INSPIRED
Paco2) obtained by analyses of the arterial blood,
to determine in normal subjects the A-a gradient
for oxygen and CO2, and to calculate the oxygen
diffusing capacity of the lung (DLO2). As seen in
Table III: (a) the 02 A-a gradient ranged between
3 and 11 mm. Hg, with an average of 6 mm. Hg;
(b) the CO2 A-a gradient varied from 6 to + 4
mm. Hg, with an average of 0.5 mm. Hg; and (c)
the DLO2 at rest ranged from 18 to 33 with an
average of 22 ml. per min. per mm. Hg.
Patients with Pulmonary Dysfunction
The results in these three patients demonstrate
that the experimental points fall, as in the normal
subjects, along a sloping straight line with a minimum of scatter. This is illustrated in Figures 6
Alveolar-arterial 02 and CO2 gradients and oxygen and 7.
diffusing capacity of the lungs
The values for alveolar tensions (PAO2 and Volume of respiratory dead space
In the three patients, VDO2 and VDCO2 were
PACO2) obtained by extrapolation were used in
and not influenced by mild exercise, by variand
equal,
tensions
blood
with
gas
(Pao2
conjunction
-
47-6
A. P. FISHMAN
Alveolar-arterial 0° pressure gradient
The A-a gradients in patient G. W., determined
in two distinct series of experiments at two levels
of arterial per cent HbO2 saturation (80 per
cent and 70 per cent, respectively) were 18 mm.
Hg (Table III). This is a much larger figure
ation in the arterial per cent HbO2, or by addition
of an external dead space. Two subjects, G. W.
and E. H., of relatively small size (Table I) had
relatively large dead space volumes. The third
subject, G. B., with a (overdistended) single
lung, had a VD equal to 160 ml.
than seen in any of the normal subjects.
In the patient E. H., with diffuse granulomatoAlveolar gas composition
the A-a
reached the high value of 35
sis,
In the patient G. W., with non-obstructive em- mm. Hg. Itgradient
is of particular interest that in the
physema, and in G. B., with a single, overdistended same subject, using the Riley-Cournand method
lung, the PAO2 and PACO2 were not significantly dif- of analysis and a 16 per cent oxygen mixture which
ferent from those observed in normals with similar resulted in a similar lowering of the arterial per
oxygen mixtures. In E. H., with diffuse granu- cent HbO2, a value of 29 mm. Hg was obtained.
lomatosis of the lung, the composition of the gas In subject G. B. with one remaining lung, the A-a
mixture required to maintain 80 per cent saturation gradient was within the normal range.
was higher, and therefore, comparison of the alThe oxygen diffusing capacity was not calcuveolar PAO2 with the normal subject is not possible. lated in the two subjects with the large A-a gradiVDO2 392
PiO2 74
-.
a
MM. HO.
ML.
X
70
- -
0
Vo02: 2 1 3 ML.
'
-H
a.h
---
60
'-~~~~~~~~~~~~~~~~~~o
o
50
THE
(A) 1 50 ML.
401
EFFECT
OF
ADDED DEAD SPACE
(B) ABDOMINAL
BINDER
so
lvft 146
SUBJECT: A.P. F.
lftb
OXIMETER SATURATION:
80 S
I%b
A.'o
,%b
a
I.,-2t
X
1
ILI0
-,I
4 "%
00
0
10,00
-I:.
.ooF
Soo
ot
.o-4-.
%b %A
333
-i.0703
VDCO2:386 ML.
%ft
-ft -
-_
-6-
.00'O4
VDCO2=2 18
200
I
VTBTPS
-
ML.
FIG. 4. APPLICATION OF THE ISO-SATURATION METHOD IN A NORMAL SUBJECT
Note that (a) addition of a measured additional dead space causes a corresponding increase in the measured
VD (see Figure 3), and (b) that change in the mid-position of the lung by an abdominal binder causes only a
slight decrease in VD.
477
RESPIRATORY DEAD SPACE AND ALVEOLAR GAS COMPOSITION
t5o I
F.
m
Pio2=I48-150.5 MM.HG.
70
0
,, op
, 40
-V
aso0
**
S~~~~~
I12
6N4
a-
VDO X228"L.
OINLUDINO 7 5 ML.
CXTERNAL DEAD $PACE
PAo2I108MLk*
,
2--
11 0
,
DETERMINATION OF DE AD SPACE
AND
ALVEOLAR GAS TENSIONS
WITHOUT ANOXIA
0OO0
401
SUBJECT: A.P.F.
Fiot
.21
30
N.e4'*
PA Cop 2 4
N
0
0
20o
S
hi
C0
I .0
k
00
0
1000
G00
333
---
.001
.002
.003
i
ML.
., -%% VDCO&211
".
26f0
i
*004
1-
200
i
.006
VT BT
.,
v
FIG. 5. APPLICATION OF THE ISO-SATURATION METHOD IN A NORMAL SUBJECT
Note that without anoxia there is a considerable scatter of the experimental points.
ents, since in the presence of pulmonary disease,
despite significant arterial per cent HbO2 unsatu-
external dead
cate that
space.
The data furthermore indi-
VDO2 is equal to VDCO2, and that, thereration, the specific contribution of venous admix- fore, in the steady state, RA = RE.
ture to the A-a gradient cannot be ascertained.
By this method, the VD in the normal male subjects averaged 164 ml., with a range from 145 ml.
In the subject with one single lung, it was calculated to be 13, a figure below the range observed to 215 ml., and in the normal female subject studied (L. D.) was 90 ml. These values correspond
in normals.
well with those recently described by other inDISCUSSION
vestigators using different methods. Thus, Fowler (6) used continuous, rapid analysis of the exRespiratory dead space
pired breath for nitrogen to identify completion
The results described above confirm those of of dead space wash-out and calculated an average
the earlier study with the iso-saturation method "physiological" VD of 156 ml. in males and 104 ml.
(1) and indicate that the volume of the respiratory in females. DuBois, Fowler, Soffer, and Fenn
dead space (VD) remains constant despite wide (7) determined "sequential" alveolar carbon dioxvariation in tidal volume (VT) and that this con- ide values by continuous analysis of the expired
stancy is maintained during a wide variety of ex- breath and obtained by substitution in the Bohr
perimental conditions, including change in the formula an average "physiological" VD of 177 ml.
composition of inspired gas and the addition of in normal males. Hatch, Cook, and Palm (8) ap-
478
A. P. FIEMIAN
THE
EFFECT
OF
SUDEOT:
DETERMINATION
VARYIt4
6.W.
ASSIST
OF
ARTERIAL
VD
PA
Hf
AD
DlAG IMPHYS9NA
iNON
EXTERNAL
Vs
OBSTRUOTIVI
I
ART.
Ll" H O S
_
Vftop=398 ML.
79- 1.
^T
TOTAL
TOTAL
409
J§
V002K VDOOIN
3af
VDCo00270 ML.
FIG. 6. APPLICATION OF THE ISO-SATURATION METHOD IN A PATIENT WITH
NON-OBSTRUCTIVE EMPHYSEMA UNDER A VARIETY OF EXPERIMENTAL CONDITIONS,
INCLUDING VARIATIONS IN DEGREE OF ANOXIA AND ADDITION OF AN EXTERNAL
DEAD SPACE
Note that alignment of experimental points and the results confirm observations made in normal subjects.
plied fractional analysis of the expired breath to
an experimental method somewhat similar in principle to the iso-saturation method, and concluded
that the average "anatomic" VD in normal male
subjects was 130 ml.
Despite the designation "anatomic" or "physiological," these volumes for VD are closely similar.
This is readily understood from a brief consideration of the Bohr formula, where VD emerges as a
function of the value and the method used for PA.
In normal resting subjects, a variety of methods
yield the same PA; in the presence of pulmonary
disease, or during deviation from the resting state,
discrepancies may be anticipated, the degree of
difference depending on the method of sampling.
Thus, the iso-saturation method, based on graphic
solution of the Bohr formula, defines a well-ventilated, non-perfused space where no measurable
exchange occurs, and in which the inspired
mixture retains its initial composition. In
normal subjects this space must closely approximate the volume of the conducting airway, the
anatomic VD.
In contrast, the VD determined by substituting
Paco2 for PACO2 in the alveolar gas equation, as
done in the Riley-Cournand method of analysis of
ventilation-perfusion relationships, (4) includes
not only this space, defined by its inspired gas
composition rather than anatomic boundary, but
also a fraction of the alveolar volume which is well
ventilated, but poorly perfused.8 In our series of
gas
gas
3 This latter volume may be schematically represented
by subdividing the total alveolar volume (VAT) of known
composition (PA.) into two virtual volumes with the following arbitrary composition: virtual volume 1 (VA1),
containing "effective" alveolar gas (Pt,A) (5) and vir-
479
RESPIRATORY DEAD SPACE AND ALVEOLAR GAS COMPOSITION
3o
PIlop=
110
1 1 2.4 -1 13.4 ".8
ML.
/VDO2=266
INCLUDING 75 ML.
EXTERNAL DEAD SPACE
6
a.
1003
0
w
XPAo28 2 MM.HG.
90
0.
DETERMINATION OF DEAD SPACE
AND
II0
ALVEOLAR GAS TENSIONS
SUBJECT:E.H. AGE:I9 DIAG: ALVEOLAR CAPILLARY BLOCK
301
OXIMETER
SATURATION
a0± 2
S
0"
to
I..
I-
0
28 m
20 PA CO?
me.H.
w
0.
I
1
VDCOp =26 4 ML.
%.OW
1- 00
0
FIG. 7. APPLICATION
10lflfl
II
.001
OF THE
333
SOO
I
.002
ISO-SATURATION METHOD IN
normal male subjects, the mean and range
of variation of VD measured (a) by the iso-saturation method and (b) by substituting Paco2 for
seven
tual volume 2 (VA2) with the same composition as inspired gas (PI.). Therefore, VAT-PA. = VA1, PAp +
VA2,PIZ. The "physiological" dead space of Riley and
Cournand is the sum of the non-gas exchanging volume
(defined by the iso-saturation method) + virtual volume
2 (VA2). In normal subjects, VA2 is very small, since
there is little inhomogeneity of ventilation and perfusion.
In short, any method for determination of VD based on
the addition of a detector gas to the inspired gas mixture,
measures a space closely approximating the anatomic VD,
plus an additional volume related to diffusion at the interface between anatomic VD and alveolar gas; the isosaturation method measures a similar volume. On the
other hand, any method! using a tracer gas which has
undergone gas exchange, such as carbon dioxide, defines a
VD which is physiologically ineffective, and is influenced
by the dynamics of alveolar ventilation and/or variations
in ventilation-perfusion relationships.
This view has been previously expressed by GrosseBrockhoff and Schoedel. Grosse-Brockhoff, F., and
Schoedel, W., Der effective schadliche Raum. Pflugers
Arch., 1937, 238, 213.
.003
A
PATIENT
WITH
1%.
1 250
)p
200 VT STPS
I
I
.004
.005
DIFFUSE GRANULOMATOSIS
OF THE
V.
LUNGS
PACO2 in the Bohr equation, were almost identical.
By the first method, the mean VD equals 164 ml.,
with the range from 145 to 215 ml., as compared to
VD equal to 174 ml., with a range from 140 to
208 ml. by the second method. The VD was also
calculated by the two methods in the three patients, since it was anticipated that differences
might appear. However, in the patient with nonobstructive emphysema, and in the patient with a
single distended lung, the VD were almost identical
by both methods. In only one patient, with considerable impairment of gas exchange due to widespread granulomatosis of the lungs, was the discrepancy very significant. In this subject, VD by
the iso-saturation method measured 189 ml., and
by the other method, 277 ml.
The alveolar-arterial oxygen pressure gradient and
diffusion constant of the lung
The alveolar gas tension obtained by the isosaturation method represents the alveolar component of expired gas (4). It differs from "ef-
A. P. FISHMAN
480
fective" alveolar gas tension which is based on the
use of arterial blood, because of contributions from
well-ventilated, poorly perfused alveoli. In normal subjects, where there is little inhomogeneity
of ventilation and perfusion, the differences between "effective" alveolar gas and the alveolar
component of expired gas fall within the errors of
the methods used for their determination.
The studies made by the iso-saturation method
were all performed during anoxia. Consequently
the calculated A-a gradient is a measure, in normals, of the failure of pulmonary capillary blood
to reach equilibrium with alveolar oxygen tension.
This gradient which averaged 6 mm. Hg with a
range from 3 to 11 mm. Hg in normal subjects,
compares well with the A-a gradient determined
in normal subjects during anoxia by Lilienthal,
Riley, Proemmel, and Franke (9).
The diffusion coefficient of the lung was calculated in the normal subjects using the A-a gradients and the Riley modification of the Bohr integration technique. The results were again similar
to those calculated independently by the RileyCournand method of analysis. Similar calculations
in the patients with pulmonary disease could not
be done since no assumption as to the negligible
effect of venous admixture on the A-a gradient
during anoxia can be made.
Clinical value of the iso-saturation method
This method makes possible the determination
of the volume of the respiratory dead (non-gas
exchanging) space, the composition of alveolar
gas and the A-a oxygen and carbon dioxide gradients during hypoxia, and the diffusion coefficient
of the lungs in normal subjects and in patients
with pulmonary dysfunction. However, the large
number of experimental points needed for each
determination, plus the high degree of cooperation
required of the subject, and finally, the necessity
of maintaining a steady state of circulation and
respiration, limit the clinical utility of this method.
respiratory dead (non-gas exchanging) space and
the alveolar gas composition in eight normal subjects and in three patients with pulmonary disease.
2. The results confirm the previous observations
on anesthetized dogs and normal human subjects,
and indicate that this dead space (VD), remains
constant over a wide range of tidal volumes and
during a variety of experimental conditions. The
average VD in the seven male subjects was 164 ml.
3. An attempt has been made to identify the
VD measured by the iso-saturation method. This
well-defined VD containing inspired gas, must be
distinguished from the virtual, "physiological" VD
calculated from blood gas tensions, which may
vary during exercise and in pulmonary disease,
due to changes in the dynamics of alveolar ventilation, and alveolar ventilation-perfusion relationships.
4. The alveolar gas compositions determined
by this method were coupled with results of direct arterial blood gas analyses for the calculation
of the alveolar-arterial (A-a) oxygen and carbon
dioxide pressure gradients. In the normal subjects, the A-a oxygen and carbon dioxide gradients
averaged 6 and 0.5 mm. Hg, respectively.
5. The A-a gradients were applied to the calculation of the oxygen diffusion capacity of the
lungs in the normal subjects; the DLO2, at rest,
was calculated to be 22 ml. per min. per mm. Hg.
6. The A-a gradient and VD were similarly studied in three patients with three different types of
pulmonary dysfunction. The A-a oxygen gradient and the VD were considerably increased in one
subject with diffuse pulmonary granulomatosis,
but were within normal limits in one patient with
chronic non-obstructive emphysema, and in another patient with a single distended lung. The
results of the VD measurements in the patient with
diffuse pulmonary granulomatosis were used to
emphasize the theoretical differences between the
VD measured by the iso-saturation method and the
"physiological" VD.
SUMMARY
ACKNOWLEDGMENT
1. The graphic solution of the Bohr formula
according to the method described by Pappenheimer, Fishman, and Borrero (1) has been applied to the determination of the volume of the
The author gratefully acknowledges the help and encouragement received from Dr. A. Cournand during the
course of these studies, and the aid of Dr. P. Samet and
other members of the Laboratory in the execution of many
of these experiments.
RESPIRATORY DEAD SPACE AND ALVEOLAR GAS COMPOSITION
REFERENCES
1. Pappenheimer, J. R., Fishman, A. P., and Borrero,
L. M., New experimental methods for determination of effective alveolar gas composition and
respiratory dead space, in the anesthetized dog and
in man. J. Applied Physiol., 1952, 4, 855.
2. Bateman, J. B., Alveolar air, respiratory dead space
and the "ventilation index." Proc. Soc. Exper.
Biol. & Med., 1950, 73, 683.
3. Riley, R. L., Proemmel, D. D., and Franke, R. E., A
direct method for determination of oxygen and
carbon dioxide tensions in blood. J. Biol. Chem.,
1945, 161, 621.
4. Riley, R. L., Cournand, A., and Donald, K. W., Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of the
lungs: Methods. 3. Applied Physiol., 1951, 4,
102.
481
5. Riley, R. L., and Cournand, A., Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of lungs: Theory. J. Applied
Physiol., 1951, 4, 77.
6. Fowler, W. S., Lung function studies. II. The respiratory dead space. Am. J. Physiol., 1948, 154, 405.
7. DuBois, A. B., Fowler, R. C., Soffer, A., and Fenn,
W. O., Alveolar CO, measured by expiration into
the rapid infrared gas analyzer. J. Applied Physiol.,
1952, 4, 526.
8. Hatch, T., Cook, K. M., and Palm, P. E., Respiratory
dead space. J. Applied Physiol., 1953, 5, 341.
9. Lilienthal, J. L., Jr., Riley, R. L., Proemmel, D. D.,
and Franke, R. E., An experimental analysis in man
of the oxygen pressure gradient from alveolar air
to arterial blood during rest and exercise at sea
level and at altitude. Am. J. Physiol., 1946, 147,
199.
ANNOUNCEMENTS OF MEETINGS
The 46th Annual Meeting of the American Society for Clinical
Investigation will be held in Atlantic City, N. J., on Monday, May
3, 1954, with headquarters at the Chalfonte-Haddon Hall. The
scientific session will begin at 9 a.m. at the Steel Pier Theater.
The annual meeting of the Association of American Physicians
will be held at the Chalfonte-Haddon Hall on Tuesday, May 4, and
Wednesday, May 5, 1954.
1/--pages
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