Decreased Affinity of Blood for Oxygen
in Patients with Low-Output Heart Failure
By James Metcalfe, M.D., Dharam S. Dhindsa, Ph.D.,
Miles J. Edwards, M.D., and Athanasios Mourdjinis, M.D.
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ABSTRACT
Oxygen affinity of blood was measured in 16 patients (nonsmokers) without
anemia and with clinical evidence of low cardiac output. Of these patients, 12
were catheterized and showed an arteriovenous oxygen concentration
difference across the lungs greater than 5 ml/100 ml. The partial pressure of
oxygen required to half-saturate their blood with oxygen (P 50 ) averaged 29.4
mm Hg (SD ± 1.9). Blood from normal subjects (nonsmokers) had an average
P.-l0 of 27.3 mm Hg (SD ± 0.9). The decreased oxygen affinity found in blood of
patients with low levels of cardiac output is considered as a compensatory
adjustment to poor tissue blood flow, promoting the diffusion of oxygen from
blood in tissue capillaries to intracellular sites of utilization.
ADDITIONAL KEY WORDS
oxygen dissociation curve
compensation for tissue hypoxia
• A decreased affinity for oxygen has been
demonstrated in blood from patients with
varied conditions including high altitude exposure (1-3), anemia of several different etiologies (4-9), and arterial hypoxemia due to
either congenital heart disease or chronic obstructive pulmonary disease (10). One physiological common denominator of these clinically dissimilar entities is an impairment in the
delivery of oxygen to tissues which is reflected
by a lowered oxygen tension in venous blood
leaving the tissues (11).
Tissue blood flow is, of course, an important
link in the chain of oxygen supply which runs
from the environmental air to the mitochondria. Patients with abnormally low levels of
cardiac output and decreased peripheral blood
flow have, like those with the other disease
conditions already mentioned, a lowered
oxygen concentration in mixed venous blood.
This paper reports the results of studies of
From the Heart Research Laboratory, Department
of Medicine, University of Oregon Medical School,
Portland, Oregon 97201.
This study was supported in part by Training Grant
HE 05499 and Research Grant HE 06042 from the
National Heart Institute and by the Oregon Heart
Association.
Received October 28, 1968. Accepted for publication June 2, 1969.
Circulation Research, Vol. XXV, July 1969
blood oxygen affinity from patients selected
because of clinical and, in most cases,
laboratory evidence of low cardiac output.
Methods
Patients were selected initially on the basis of
clinical evidence of low cardiac output secondary
to long-standing valvular heart disease. Patients
with pulmonary or peripheral edema were
excluded, as were smokers and patients whose
blood oxygen capacities were lower than 17.0
ml/100 ml. Subsequently, in order to evaluate the
data quantitatively, patients with clinical evidence of low cardiac output who were being
subjected to cardiac catheterization were studied
if the catheterization data showed an oxygen
concentration difference between arterial and
mixed venous blood greater than 5 ml/100 ml at
rest.
For each study of blood oxygen affinity, venous
blood was drawn without stasis into a syringe
containing a solution of sodium fluoride and
heparin. Equilibrium values of oxygen hemoglobin were determined using the "mixing technique" (12) at a carbon dioxide pressure (Pco 2 )
of approximately 40 mm Hg and at 37°C. At least
two values of blood oxygen pressure (Po2) and
pH, one between 40% and 50% saturation and the
other between 50% and 60% saturation with
oxygen, were determined in each study. The
observed values of Po2 were corrected to a
standard plasma pH of 7.40 (13) and plotted on
linear coordinates at saturation values calculated
for each mixture by correcting for dissolved
47
METCALFE, DHINDSA, EDWARDS, MOURDJINIS
48
TABLE I
Cardiac Output, Arteriovenous Oxygen Concentration Differences, and Blood Oxygen Capacities of Patients with Low-Output Heart Failure with Calculated Values for P 50
Patient
Cardiac output
(L/min/m')
J. A.
B. J.
B. L.
E. L.
L. E.
E. W.
A. J.
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
K. B.
F. E.
D. G.
L. C.
S. L.
S. D.
H. L.
W. T.
B.C.
MEAN
± SD
Cao, - c *o,
(ml/100 ml)
1.4
2.3
1.7
2.4
2.2
3.5
2.0
2.3
1.9
2.8
2.2
2.2
10.5
2.2
0.5
G.9
1.3
7.8
7.4
0.2
G.I
5.8
G.8
G.7
7.5
5.4
6.5
0.3
Oxygen capacity
(ml/100 ml)
(mm Hg)
17.1
19.0
19.5
19.8
17.4
19.2
24.3
18.5
20.4
21.3
19.2
17.5
18.5
17.9
19.3
17.1
32.0
29.0
29.0
30.9
33.1
29.0
27.9
29.0
2C.8
20.8
20.8
29.2
30.0
31.8
30.8
27.9
19.1
29.4
1.8
1.9
Pso
For details see text.
oxygen with respect to: (a) the Po2 value in each
component of the mixture, (b) the hemoglobin
concentration of the blood being studied, and (c)
the Poo of the resultant mixture. No improvement
in the accuracy of determining the oxygen
pressure at 50% saturation (Pr,0) was obtained in
our hands by plotting values close to 50%
saturation according to Hill's equation (14). All
studies were completed within 3 hours of blood
withdrawal.
Results
As shown in Table 1, blood from patients
with clinical evidence of low cardiac output
and high values for arteriovenous oxygen
concentration difference showed a decreased
oxygen affinity (increased Pso)- The mean ±
SD of P50 values obtained by studying blood
from 11 normal subjects (nonsmokers) was
27.3 + 0.9 mm Hg (10). The corresponding
value obtained on blood from the patients was
29.4 ± 1 . 9 mm Hg. The difference is highly
significant (P< 0.01). There was a normal
degree of heme-heme interaction as judged by
the value of Hill's n (mean 2.48 ± 0.22 [SD]
compared to 2.64 ± 0.17 in blood from normal
subjects) (10).
Discussion
The availability of oxygen to its sites of
utilization in tissue cells depends upon the
constancy of the external environment and
also upon an integrated series of supply
mechanisms which include ventilation, diffusion across the alveolocapillary membrane,
transport from lungs to tissue capillaries, and
diffusion from capillary blood to intracellular
enzyme chains. The last of these processes is,
according to evidence currently available, a
passive (physical) process whose rate depends upon several physiological variables
including the mean diffusion distance, the
surface area for diffusion, and the gradient of
oxygen tension between capillary blood and
tissue cells. Present evidence (15) suggests
that the level of intracellular oxygen is at most
only a few millimeters of mercury, so the
gradient for oxygen delivery depends largely
upon the oxygen tension in capillary blood.
That tension is, in turn, regulated (at a fixed
rate of tissue oxygen consumption) by the rate
of hemoglobin flow (the rate of blood flow
multiplied by the oxygen-carrying capacity of
Circulation Research, Vol. XXV, July 1969
BLOOD OXYGEN AFFINITY AND HEART FAILURE
49
100
90
02
Extraction 21%
Normal
80
I
Patients
with
Low Cardiac Output
TO
• Extraction
38%
!*o
.5 50
5
I
40
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20
10
10
20
30
40
50
60
P 0 2 mm Hg
70
80
90
100
FIGURE 1
Average oxygen dissociation curves of blood from normal subjects and from patients with low
levels of cardiac output determined at a temperature of 37°C. All values were corrected to a
plasma pH of 7.40. The increased oxygen extraction characteristic of patients with low rates
of blood flow is shown. The values of Po2 which are indicated on the curves represent mixed
venous blood (see text).
blood) and by the position and shape of the
blood oxygen dissociation curve.
Evidence has been presented, derived from
comparative studies (16), for a remarkable
similarity of values for oxygen tension in
mixed venous blood from varied species at rest
over a wide range of body sizes and rates of
oxygen consumption. We have interpreted this
similarity as indicating a uniformity of oxygen
tension in the "average" tissue capillary of the
resting animal over the recent course of
evolution. It is achieved by appropriate
regulation of the rate of hemoglobin flow
according to the oxygen affinity of blood and
the rate of oxygen consumption characteristic
of each species.
Changes in the oxygen affinity of blood
(expressed at standard values of plasma pH
and temperature) occur in humans when
Circulation Rejearch, Vol. XXV,
July 1969
tissue oxygen supply is handicapped by
residence at high altitude or by any of several
diseases. The data presented here show that
this adaptation is employed by patients whose
tissue oxygen supply is compromised by low
rates of blood flow secondary to heart disease.
The utility of the observed change in maintaining the oxygen tension of blood in the
average capillary is illustrated by Figure 1.
The patients we studied extracted, on the
average, 38% of the oxygen from their arterial
blood during transit through peripheral tissues. This extraction contrasts with one of 21%
in normal individuals (11). Because of the
rightward displacement of the blood oxygen
dissociation curve, the increased extraction
would lower the oxygen tension in mixed
venous blood from the value of 40 mm Hg
which is found in normal resting humans (11)
50
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to approximately 33 mm Hg. If their blood had
retained a normal affinity for oxygen, the
mixed venous oxygen tension would have
fallen to 30 mm Hg with an oxygen extraction
of 38%. Displacement of the blood oxygen
dissociation curve, by itself, prevents about
30% of the fall in venous blood oxygen tension
that would occur in patients with this degree
of limitation of cardiac output if their blood
oxygen affinity did not change. It is important
to note that other mechanisms, such as
changes in hydrogen ion concentration, also
influence oxygen affinity. For instance, metabolic acidosis would displace the curve still
further to the right, acting additively to the
change reported here to support oxygen
tension in tissue capillaries.
We regard lowered oxygen affinity of blood
as an adaptive mechanism available to the
human organism when its tissues are threatened with hypoxia. A 33% increase in cardiac
output would elevate mixed venous oxygen
tension to 33 mm Hg without the observed
change in oxygen affinity, but seems to be an
unavailable or, at least, less acceptable alternative for patients with low output heart
failure.
A possible mechanism for changes in
oxygen affinity found in blood from patients
threatened with tissue hypoxia is suggested by
the work of Benesch and Benesch (17),
showing that deoxygenated hemoglobin removes 2, 3-diphosphoglycerate from its free
state in the red cell and stimulates glycolysis
to replenish the erythrocyte's stores of it and
other organic phosphates. 2, 3-Diphosphoglycerate has been shown to decrease hemoglobin's affinity for oxygen (18, 19), and on the
basis of these findings, we have previously
postulated (10) that changes in its concentration within the erythrocyte are responsible for
the changes in blood oxygen affinity seen in
patients whose tissues are threatened with
hypoxia, as indicated by abnormally low
values for oxygen saturation in mixed venous
blood. Levels of 2, 3-diphosphoglycerate have
recently been shown to increase in the red
cells of humans within 36 hours of beginning
sojourn at high altitude (3). Although
METCALFE, DHINDSA, EDWARDS, MOURDJINIS
changes in its concentration within the red cell
seem at present to offer the most attractive
hypothesis for the changes observed in these
patients with low cardiac output, other
modifications in the environment of hemoglobin, such as increased acidity (20, 21), cannot
be discarded as possibilities.
A vital function of the circulation is to
maintain an oxygen tension in peripheral
capillary blood adequate to supply oxygen to
intracellular sites of utilization. Capillary
oxygen tension depends upon the rate of
blood flow with respect to oxygen consumption and upon the respiratory characteristics
of circulating blood including oxygen affinity.
In considering the therapeutic management of
a patient with restricted cardiac output, the
oxygen affinity of blood should be regarded as
subject to regulation. For example, blood
stored under usual conditions shows a definite
increase in oxygen affinity within a few days
(22) and the high affinity persists at detectable levels for several hours after transfusion
(5). Such blood, when used in the treatment
of shock, is predictably less effective in
delivering oxygen to tissues than blood with
normal or decreased oxygen affinity would be.
Similarly, exposure to carbon monoxide at
levels experienced by smokers causes both an
increase in blood oxygen affinity and a
decrease in the concentration of functional
hemoglobin (23). For both reasons, smoking
jeopardizes tissue oxygen supply. Procedures
for maintaining tissue oxygenation should take
into account factors that influence blood's
oxygen affinity as well as those that maintain
blood's oxygen capacity.
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Decreased Affinity of Blood for Oxygen in Patients with Low-Output Heart Failure
JAMES METCALFE, DHARAM S. DHINDSA, MILES J. EDWARDS and ATHANASIOS
MOURDJINIS
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Circ Res. 1969;25:47-51
doi: 10.1161/01.RES.25.1.47
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