From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
Effect
By Arthur
of Smoking
L. Sagone,
on Tissue
Jr., Thomas
Lawrence,
HRONIC
EXPOSURE
in man
as a result
and
Stanley
P. Balcerzak
data suggest
that chronic
exposure
to
levels of CO results
in tissue
hypoxia,
probably
as a result
of decreased
blood
oxygen
carrying
capacity
and increased
blood-O2
affinity.
Adaption
is reflected
in an
increased
ACM and not by intraerythrocytic
low
changes.
The response
in ACM may be to
levels
seen In polycythemla
vera, as evidenced
by a value of 37.6 in one smoker
whose ACM fell to normal after discontinuing cigarettes.
This
study
indicates
that
smoking
causes
mild erythrocytosis
comparable
to that seen in spurious
or stress
polycythemia.
It also suggests
that chronic
exposure
to low levels of CO may further
embarrass
tissue
oxygen
supply
in patients
with anemia,
heart
disease,
chronic
lung
disease,
and cerebral
vascular
disease
In
whom oxygen
delivery
to tissues
is already
marginal.
to carbon
monoxide
(CO)
industrial
wastes,
automobile
of
Supply
These
The purpose
of this study was to determine
if chronic
exposure
to low levels of carbon
monoxide
(CO) in man results
In tissue hypoxia.
For this reason,
nine smokers
(more
than one pack of cigarettes
per day) were
studied.
The
presence
of hypoxia
was
assessed
by measurement
of red cell mass
(ACM).
The effect
of CO on lntraerythrocytic factors
involved
with oxygen
delivery
was determined
by measurement
of oxygen-hemoglobin
affinity
(P5o) and of red
cell 2,3-diphosphoglycerate
(DPG) and adenosine
triphosphate
(ATP).
Values
were
compared
to those
of 18 nonsmokers
of
similar
age, sex, and race. Values
for carboxyhemoglobin
(COHb),
RCM,
hemog!obin, hematocrit,
and red cell count
were
significantly
higher
in the smokers.
DPG
levels were unaltered,
while
P50 and ATP
levels
were
significantly
lower
in smokers.
C
Oxygen
is occurring
ing.’3
Although
such
exp )sure
produces
relatively
low
hemoglobin
(COHb)
with
oily
a minor
decrease
in oxygen
CO
also
enhances
oxygen-hemoglobin
oxygen
delivery
could
supply
and to provoke
Reports
of increased
through
their
occupation”2
fact,
occur
does,
in
could
result
cell
red
mass.
smokers
From
the
The
Submitted
June
in
Fund.
Arthur
43210.
1972;
by
revised
the
Jr., M.D.:
Assistant
Medicine,
Columbus,
rather
increase
the
State
accepted
Association
ervthrocytosis
hematocrits
from
an
increased
red
cell
mass
presumably
Ohio
4, 1972;
Heart
that
than
in
is in response
University
October
College
17,
70-34
Grant
in
tissue
oxygen
red cell mass.
those
exposed
increased
that
Oncology,
October
L. Sagone,
suggest
these
demonstrates
and
Ohio
of
Balcerzak,
State
University
M.D.:
Oncology,
Blood,
Hematology
Central
Ohio
©
of
CO
volume,
Although
Ohio
of
smokcarboxycapacity,
abnormalities
significantly
with
such as an increased
smokers5’#{176} and
in
However,
study
two
These
and
levels
of
carrying
of
1972.
and
United
Health
1971.
College
The
28,
part
levels
plasma
present
Division
low
settings.
increased.
Columbus,
Supported
these
a decreased
is actually
Medicine,
to
in
from
affinity.4
combine
to interfere
adaptive
responses,
hematocrits
in
increasingly
exhaust,
The
1973
Vol.
by
Professor
Ohio
Grune
41,
No.
State
& Stratton,
6 (June),
Professor
Ohio
College
of
of
Medicine,
Medicine
University
of
College
Medicine,
Thomas
43210.
and
Columbus,
Director,
of
The
Lawrence:
Medicine,
Ohio
State
University
Pre-doctoral
Ohio
Division
Columbus,
Trainee,
Stanley
Hematology
43210.
of
Ohio
P.
and
43210.
Inc.
1973
845
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
846
to
SAGONE,
tissue
hypoxia,
evidence
2,3-diphosphoglycerate
adaptation
may
that
smoking
syndrome.
of
intraerythrocytic
(DPG),
exaggerate
may
be
was
the
one
LAWRENCE,
not
adaptation
found.
erythropoietic
cause
of
MATERIALS
AND
This
response.
spurious
AND
to
lack
BALCERZAK
hypoxia,
i.e.,
of intraerythrocytic
These
findings
erythrocytosis
or
suggest
Gaisb#{246}ck’s
METHODS
Subjects
Twenty-seven
study.
Nine
study
group;
had donated
healthy
white
men
who smoked
the remaining
18
blood
during
the 6
men between
the ages of 20 and 32 participated
in this
one or more
packs
of cigarettes
per day constituted
the
men were nonsmokers
and served
as controls.
No subject
mo prior to study.
Procedure
The
subject
DPG,
blood
following
studies
on the morning
carboxyhemoglobin
collected
in ACD
were done on the same venous
blood
sample
collected
of the study:
blood
counts,
red cell adenosine
triphosphate
(COHb)
levels,
and oxygen-hemoglobin
curves.
An
and tagged
with Na251CrO4
was used for measurement
from
each
(ATP),
aliquot
of
of red cell
mass.
Specific
methods.
(1)
Hemoglobins,
hematocrits,
reticulocyte
counts,
red
cell
counts,
and platelet
counts
were done
by standard
techniques.7
(2) COHb
levels
were
measured
directly
with an IL Model
182
CO-oximeter.8
(3) Red cell mass
was
determined
by the
Na95CrO.1
method.9
Values
were expressed
as milliliters
per kilogram
of body weight,
per
centimeter
of height,
and per square
meter
of body
surface.
No correction
was made
for
plasma
trapping.
(4) Erythrocyte
DPG
was
determined
enzymaticallylO
and
was
expressed
as ,moles/g
of hemoglobin.
(5) Erythrocyte
ATP was determined
fluorometrically
by the
firefly method11
and was expressed
as ,zmoles/g
hemoglobin.
(6) Arterial
blood
gases
were
measured
with a radiometer
blood
gas system
on brachial
artery
blood
collected
anaerobially
in
heparin.
(7)
Oxygen-hemoglobin
dissociation
curves
were
determined
by a
spectrophotometric
method,
employing
a tonometer
cuvette
in which
a dilute
suspension
of whole
blood
in phosphate-buffered
saline
(pH 7.4) is used
to determine
oxygenhemoglobin
affinity
at 37#{176}C.
Deoxygenation
was
accomplished
by
a short
exposure
of
the
suspended
red
cells
to
a
vacuum.
Bubbling
was minimized
by cooling
the suspension
in an ice bath prior
to brief
evacuations,
with
further
degassing
accomplished
by rewarming
the solution.
Known
quantities
of air were then added
to the tonometer,
and the spectrum
of the solution
was
determined
at several
oxygen
tensions
on a Cary
model
15 recording
spectrophotometer.
The technique
of air addition
and
the calculation
of oxygen
saturation
and
tension
were
identical
to those
described
by Benesch
et al.12
An oxygen-hemoglobin
curve
was
determined
on the basis
of at least
five points.
Oxygen
affinity
was expressed
as the
partial
pressure
of oxygen
at 50%
saturation.
The reliability
of this method
to determine
the effect
of COHb
on oxygen-hemoglobin
affinity
was tested
in three
ways.
(1) The
effect
of levels
of COHb
from
5%-20%
on oxygen-hemoglobin
affinity
was
determined
on intact
human
red cells.
Venous
blood
was collected
in heparin
from
a
normal
nonsmoking
man
and
was
centrifuged
to
remove
the
plasma;
the
red
cells
were
washed
twice
with
normal
saline.
The
cells
were
resuspended
in normal
saline
to a
hematocrit
of 40%-50%.
An aliquot
of these
cells
was
exposed
to CO for 15 mm.
The
treated
suspension
was then diluted
with untreated
red cells to make
a suspension
of red
cells with COHb
levels
from 5% to 20%. COHb
levels
were determined
on the blood,
and
oxygen-hemoglobin
affinity
was measured.
A 1 mm Hg shift
in the
P50 was
found
per
5% COHb
in the range
from
5% to 20%.
This
is similar
to results
reported
by other
investigators.1314
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
SMOKING
AND
TISSUE
OXYGEN
SUPPLY
847
lbs
SE-bIEAN
$({lICAN
SC
D
NON-SMOKtb$
‘45
S
COMb
Sc
201
1101
SMOKERS
Fig.
(COHb)
1 . Percentage
carboxyhemoglobin
in smokers
and nonsmokers.
Suspensions
of red cells
after
the vacuum
extraction,
determination.
(3) COHb
levels of red cells
(2)
and
the
HE MATOCR IT
NON-SMOKERS
always
found
to
be
greater
Fig.
values
with 100%
indicating
were
than
that
measured
80%
of
2. Hematocrit
in smokers
and
had the same
no loss of CO
COHb
after
the
and red cell
nonsmokers.
absorption
spectra
occurs
during
this
completion
initial
RED
of
the
procedure
mass
before
part of
and
were
value.
RESULTS
Carboxyhemoglobin
The
Levels
COHb
In eight
Fig.
1.
4%
and
6.8%.
cigarettes
count
smokers
±
Red
Cell
The
the
a value
of
5.50
Since
9.2%.
one
smoked
they
represent
smoking
group
and
two
these
two
to
three
values
were
packs
of
packs
of
determined
minimum
COHb
levels.’5
is significantly
higher
than
The
the
group.
significantly
mean
group
counts
of
between
who
can be seen
in
were
between
Counts
value
Similarly,
the control
reticulocyte
smoked
individual
nonsmoking
had
The
nonsmokers.
5838
had
of the
Smokers
cell
day
Blood
2).
One
blood
samples,
of 6.2%
in the
value
Peripheral
individuals
day.
per
on morning
mean
value
( Fig.
These
per
cigarettes
1.0%
levels
in both
the smokers
and
nonsmokers
of nine
smokers,
the morning
levels
of COHb
the
X
higher
in
mean
106/cu
values
were
was
in
values
as
47.4%,
hemoglobin
mm
of 15.7
similar
than
in nonsmokers.
1076/cu
mm.
hematocrit
smokers
level
smokers
of
were
than
nonsmokers
compared
16.6
g/100
significantly
to
45%
in
ml
and
red
higher
than
g/100
ml and 5.08 X 106/ cu mm. Platelet
in both
groups.
White
counts
were
higher
Respective
mean
values
were
7457
±
1119
and
in
and
Mass
mean
nonsmokers
red
cell
(Table
mass
1).
in
This
the
smokers
difference
was
in
significantly
red
cells
greater
mass
would
than
be
in
even
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
SAGONE,
848
Table 1. Mean Red Cell Mass Values
LAWRENCE,
In Smokers
AND
BALCERZAK
and Nonsmokers
ACM/kg
ACM/sq
Mean
SD
28.6
±2.9
1132
±91
12.0
±1.0
Range
23.3-33.9
973-1319
10.0-13.6
31.8
±3.2
1321
±116
14.9
±1.4
26.0-37.6
( 0.05
1201-1581
<0.001
12.1-17.6
<0.001
in
RCM/cm
NONSMOKERS
SMOKERS
Mean
SD
Range
P
Values
for nonsmokers
are similar
to those
reported
were
expressed
for normal
men by other
investlga-
tors.23-25
more
striking
The
if the
mean
than
mean
group
m
can
greater
group.
in
1300
ml/sq
of
Fig.
evidence
178.5
2.
Six
m,
had
fact
was
of
as
that
not
the
packs
per
all the
of pulmonary
value
of
cythemia
red cell
of
and
had
1581
ml/sq
m
in hematocrit
his hematocrit
at 86
seen
was
cm.
Individual
smokers
spite
of
red
1
of
outside
in this
disease,
blood
The
mass
the
nonsmoking
in
ml/kg),
a level
were
after
ml/sq
50%
to
.
47%
Six
this
per
values
controls
healthy
young
and
P02)
cell masses
and
in these
persons
smoked
two
to
highest
red
cell
mass
seen
in
poly-
to
that
cessation
of smoking,
m (33 ml/kg),
with
During
45%.
the
PCO2
red
similar
values
of
(pH,
the
the
the
mass
range
who
that
than
cell
gases
had
fact
lower
cell
study
subject
of 9.2%
mass.
higher
red
18
the
subjects
the
slightly
had
with
were
level
months
to 1381
from
was
in
and
body
significantly
this
three
subject’s
a corresponding
months
after
he stopped
period
his weight
remained
kg.
Oxygen-Hemoglobin
As
(37.6
kg,
cm
of lean
was
with
the highest
that
the erythrocytosis
hypoxemia.
a COHb
rubra
vera.
Three
mass
haddecreased
decrease
smoking,
stable
result
day
73.6
nine
that
measured
in the three
smokers
found
to be normal,
indicating
was
and
compared
values
in terms
kg
82.3
value
of
was 176.7
height
seen
to the
without
were
were
mass
smokers
group
mean
the smokers
smokers
in this study.
In addition
cell
the
mean
be
than
Four
men
red
of
the control
height
in
control
sq
weight
in
significantly
Affinity
Fig.
lower
was
(5.15
significantly
&moles/g
12.7
moles/g
3,
the
than
and
mean
the
lower
in
Hb)
(Fig.
Hb
(Fig.
Red
Pso
Cell
value
control
mean
smokers
4).
The
(4.50
Organic
was
23.1
value
mm
of 24.2
,moles/g
mean
Phosphate
value
for
Hb)
DPG
Levels
Hg
mm
in
Hg.
than
in
in both
the
smokers,
Red
cell
ATP
nonsmokers
groups
was
5).
DISCUSSION
This
cigarettes
identical
elevated
study
per
indicates
that
day
an
have
those
increased
who
red
group
of nonsmokers.
This
increased
hematocrit
values
found
in smokers
smoke
cell
more
mass
than
when
one
compared
pack
to
of
an
red cell mass
accounts
for the
in this and other
studies.56
The
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
SMOKING
AND
TISSUE
OXYGEN
SUPPLY
849
{-
SE
mm
Fig. 3. Red cell oxygen
affinity
in smokers
and nonsmokers.
Values
are expressed
in
terms
of oxygen
tension
required
to half
saturate
hemoglobin
with oxygen
(P50).
MEAN
Hg
SMOKERS
‘P
S.E..(
S
.
.
0
E
*
Fig.
(DPG)
4. Red
values
cell
2,3-diphosphoglycerate
in smokers
SMOKERS
and nonsmokers.
S E
NON
{ ..
-
SMOKERS
MEAN
I
..
E
A
Fig. 5. Red cell adenosine
(ATP) values
in smokers
and
triphosphate
nonsmokers.
SMOKERS
NON
- SMOKERS
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
SAGONE,
850
increase
in
oxygen
supply.
carrying
The
red
cell
capacity
of
three
with
is best
hypoxemia,
smokers
because
red
evidence
against
given
in a recent
hypoxemia
report
by
hematocrit
in
level
results
smokers
cell
masses
as
Isager
smokers
not
be
were
had
not
be
impaired
by
COHb.
explained
men
blood
erythrocytosis
who
show
correlated
tissue
oxygen
caused
young
normal
BALCEAZAK
decreased
readily
healthy
the cause
of
and Hagerup,
could
to
from
affinity
could
all
AND
a response
supply
oxygen-hemoglobin
these
highest
as
oxygen
increased
in
the
explained
tissue
and
erythrocytosis
basis
mass
Impaired
LAWRENCE,
the
the
gases.
in
that
with
on
and
the
Further
smokers
increased
altered
is
pulmonary
function.6
One smoker
polycythemia
in our study
had a red cell mass
rubra
vera.
This
suggests
that
might
be primarily
the
result
erythrocytosis
and
Hammond
some
reported
smokers.5
crits
that
hematocrits
Furthermore,
reported
by
Russell
and
Conley
to be smokers.’#{176} Although
followed
by hypoxemia
that
erythrocytosis
may
studies
are
necessary
to determine
phosphate
levels
a result
of high
altitude,’7
disease.2#{176} Our
occurs
to the
significantly
finding
and
a result
hypoxic
may
has
been
this
importance
affinity
as
anemia,18
lower
mean
the unaltered
red
DPG
may
their
of
the
no
adaptive
Gaisb#{246}ck’s
of
a
result
patients
of
in
as
were
a primary
increased
who
are
red
and
intraerythrocytic
CO
exposure.
subjects
cell
hypoxic
disease,’9
as
heart
adaptation
In fact,
a
in smokers.
This
exposure
to CO as
this
adaptive
response
disease.
Kjeldsen
has
response
in
hemato-
syndrome
smoking
pulmonary
significant
with
chronic
occur
high
may cause
pulmonary
results
presented
herein
of COHb
alone.
Further
cell AT!’
level
was
found
level suggest
that
chronic
impair
primary
may
of
in
chronic
52%
unexplained
cases
described
data
indicate
that
hypoxia
associated
of smoking
as a result
impair
as
than
to levels
seen in
of unexplained
smoking.
Eisen
with
smoking
eventually
and erythrocytosis,
occur
on the basis
cause
of spurious
erythrocytosis.
Decreased
oxygen-hemoglobin
organic
greater
of 25 patients
21
known
disease
indicate
comparable
some
cases
of cigarette
in those
reported
already
that
CO
exposed
to
acutely
high
altitude.2’
Benesch
red
cell
and
DPG
Benesch
and
binding
of
binding
hypoxia
of DPG
produced
reduced
hemoglobin,
postulate
ATP
these
levels
organic
phosphates
for COHb
as a result
no
that
occurring
the main
in most
mechanism
hypoxic
states
for increased
is increased
reduced
hemoglobins.22
Since
to
is similar
to that
for
of CO is not associated
alteration
of
red
oxyhemoglobin22
with
increased
cell
organic
Bishop
for
phosphate
the
and
red
the
cell
would
be
expected.
ACKNOWLEDGMENT
The
authors
gratefully
acknowledge
Mrs.
Judy
her
technical
assistance.
REFERENCES
1. Goldsmith
JR: Carbon
monoxide.
Science 157:842, 1967
2. Cooper
AG: Carbon
monoxide:
A bibliography
with
abstracts.
Public
Health
Serv-
ice Publication
U.S. Department
Welfare,
1966,
3. Committee
No.
1530.
of
Health,
p 400
of Effect
Washington,
Education
of
D.C.,
and
Atmosphere
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
SMOKING
AND
TISSUE
OXYGEN
Contaminant
on Human
Health
and We!fare : Effects
of
chronic
exposure
to low
levels of carbon
monoxide
on human
health
behavior
and
performance.
Washington,
D.C.,
National
Academy
of Science
and
Engineering,
1967
4. Barlett
P : Pathophysiology
of exposure
to low concentrations
of carbon
monoxide.
Arch Environ
Health
16 :719, 1968
5.
Eisen
ME, Hammond
EC : The effect
on packed
cell volume,
red cell
counts,
hemoglobin
and
platelet
counts.
Can Med Assoc
J 75 :520, 1956
of smoking
6. Isager
H,
between
cigarette
cell volume
and
J Haematol
8:241,
7. Sagone
AL
of iron-containing
and granulocytes
deficiency.
Am J
Hagerup
L : Relationship
smoking
and high packed
haemoglobin
levels.
Scand
1971
Jr, Balcerzak
SP : Activity
enzymes
in erythrocytes
in thalassemia
and iron
Med Sci 259 :350, 1970
8. Mass
AHJ, Hameline
ML, Leeow
RJM:
An
evaluation
of the
spectrophotometric
determination
of Hb02
HbCO
and Hb in
blood
with
the Co-oximeter
IL-182.
Clin
Chim
Acta 29 :303, 1970
9. Sterling
circulating
radioactive
K, Gray
red
cell
chromium.
851
SUPPLY
SJ: Determination
of
volume
in man
by
J Clin Invest 29:1614,
1950
10.
Beutler
E, Meul
A, Wood
L: Depleand
regeneration
of 2,3 disphosphoglyceric
acid
in stored
red
blood
cells.
Transfusion
9 :109, 1969
tion
11. -, Baluda
M : Simplified
determination of blood
adenosine
triphosphate
using
the firefly
system.
Blood
23 :668, 1964
12. Benesch
R, MacDuff
C, Benesch
R:
Determination
of oxygen
equilibrium
with
a new
versatile
tonometer.
Anal
Biochem
11:81,
1965
13. Joels N, Pugh
L: The carbon
monoxide dissociation
curve
of human
blood.
J
Physiol
(Lond)
142:63,
1958
14. Roughton
F, Darling
R: Effect
of
carbon
monoxide
on the
oxyhemoglobin
dissociation
curve.
Am
J Physiol
141:17,
1944
15. Mcllvaine
P, Nelson
WE, Bartlett
D:
Temporal
variation
of carboxyhemoglobin
concentrations.
Arch
Environ
Health
19:83,
1969
16. Russell
R, Conley
CL: Benign
polycythemia
: Gaisbock’s
syndrome.
Arch
Intern Med 114:734,
1964
17. Rodman
T, Close
H, Prucell
M : Oxyhemoglobin
dissociation
curve
in anemia.
Am J Med 52:295,
1969
18. Lenfant
C et a!. : Effects
of altitude
on oxygen
binding
by hemoglobin
and on
organic
phosphate
levels.
J CIm
Invest
47:2652,
1968
19. Edwards
MJ, Novy
MJ, Walters
C,
Metcalfe
J : Improved
oxygen
release
: An
adaptation
of mature
red cells to hypoxia.
J Clin Invest
47:1851,
1968
20. Oski F, Gottlieb
A, Miller
W, Delivoria-Papadopoulos
M: Effects
of deoxygenation of adult
and fetal hemoglobin
on the
synthesis
of red cell 2,3-diphosphoglycerate
in vivo consequences.
J Clin Invest
49:400,
1970
21. Kjeldsen
K, Damgaard
F : Influence
of
prolonged
carbon
monoxide
exposure
and
high
altitude
on the composition
of
blood
and urine
in man.
Scand
J Clin Lab
Invest
22 (Supol.
103) : 20, 1968
22. Benesch
R, Benesch
R : Intracellular
organic
phosphate
as regulator
of oxygen
release
by haemoglobin.
Nature
(Lond)
22:
618, 1969
23. Brown
5, Gilbert
H. Krauss
5, Wasserman
L : Spurious
(relative)
polycythemia:
A nonexistent
disease.
Am J Med
50:200,
and
its
1971
24. Retzlaff
J, Tauxe
W, Kiley J. Stroebel
Erythrocyte
volume,
plasma
volume
and
lean body
mass
in adult
men and women.
Blood
33:649,
1969
25. Weil J, Jamieson
C, Brown
D, Grover
R, Balchum
D, Murray
J: The red cell mass
-arterial
oxygen
relationship
in normal
man. J Clin Invest
47:1627,
1968
C
:
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
1973 41: 845-851
Effect of Smoking on Tissue Oxygen Supply
Arthur L. Sagone, Jr., Thomas Lawrence and Stanley P. Balcerzak
Updated information and services can be found at:
http://www.bloodjournal.org/content/41/6/845.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of
Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.