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Some physiologic features of atrial septal defect
Some Physiologic Features of Atria1 Septal Defect Observations in 38 Adult Patients* PAUL WINCHELL, M.D. and FOUAD BASHOUR, M.D., PH.D. Minneapolis,
T
HE APPLICATION of hypothermia cardiac
surgical problems
the repair
of atria1 septal
this group and in the cases to be presented
to certain
cator dilution
has made possible
defects
Minnesota
employed.
in the adult
indi-
curves have not been extensively
Recently,
indicator
dilution
curves
with an operative mortality of less than 10 per Using the hypothermia technic, open cent.’
utilizing Renografin+ or human serum albumin made radioactive with 1131 as a tracer isotope
atria1 septal defect repair
have been included
a group
of 38 adult
has been achieved
patients.
These
in
in the routine
thus far have not, for practical
patients
ranged in age from 16 to 61 years and of the to-
great value.
tal group, 20 have been restudied
samples taken at the time of heart
graphic,
was examined
or deny
atria1 septal
defect
and
the
Manometric
but
analysis of the blood catheteriza-
tion has been carried out.
operation. Each patient to confirm
following
studies
purposes, been of
the
by roentgen,
cathseterization
It should
preoperatively
clinical
diagnosis
at the outset
in either
Only
that
error is involved in the application
of the Fick law to the calculation
electrocardio-
methods.
be emphasized
considerable
of
the systemic
and especially
of volume flow
or pulmonary
circulation
so in the presence of large left-to-
patients in whom the diagnosis was confirmed at The data operation are included in this report.
right shunts.2
thus are not confused
blood within the right side of the heart is not per-
by the inclusion
of mal-
that may closely imitate
atria1 septal
fect,
defect, such as partial anomalous venous return to the right atrium,
pulmonary aortic sinus
the right ventricle
formations
aneurysm
with rupture
ventricular petence,
septal
defect
into
the right
atrium,
with tricuspid
incorn:
or atrioventricularis
communis
especially
It is well known that mixing
therefore
in the right
but also in artery.
It is ar-
unlikely that any single pulmonary
tery blood sample nous sample. is involved
defects.
atrium
and pulmonary represents
a true mixed
The same type of sampling
in drawing
veerror
blood from any systemic
Of the total group, only two of the atria1 defects
artery
were of the ostium primum variety and in only two instances was significant mitral valvular
smaller than in the pulmonary circuit. In calculating systemic blood flow in the pres-
disease also present.
ence of a left-to-right
used in studying
the variation
the venous sample
METHODS The methods
although
of
in such samples is
shunt, it is necessary to use in the chamber
proximal
to
the shunt as the mixed venous sample. In the case of atria1 septal defect, this would be either
these patients
vena cava or, if possible, an average value from both venae cavae. Since volume flow and blood
have been the standard procedures. Angiocardiography has not been used regularly in
* From the Departments of Medicine, University of Minnesota, Minneapolis, and American University, Beirut, Lebanon. t E. R. Squibb & Co. DECEMBER,
1958
687
Physiologic
688 oxygen
content
Features
of Atria1
in the two venae cavae are not
identical,
average values may involve considerProbably the errors inherent in error.3
able
measuring
oxygen uptake are inconsequential
compared
to those related
to blood
as
sampling.
All of these values are used in the calculation both systemic and pulmonary Fick principle
and obviously
computations
must
only. cal
as estimates
It is only fair to point out that any clinimethod
from
the results of such
for calculating
perfect
and
that
blood
flow is far
fundamental
exist relative to indicator
problems
dilution,4 arterial
pulse
PREOPERATIVE OBSERVATIONS Measurements pulmonary
have been made of systemic and
blood flow, pulmonary
sure, systemic arterial saturation,
Volume
arterial
pres-
oxygen uptake,
flow in both circuits, resistance,
been calculated. in Table
pressure work have
The pertinent
data are given
I.
Systemic Flow:
In order to calculate
TABLE 1
to know the oxygen up-
take, the oxygen content
of a mixed venous sam-
ple proximal
to the shunt, and the oxygen con-
tent of the pulmonary
venous blood which,
the normally
saturated
patient
to left shunt,
is assumed
oxygen content
without
-
to be the same as the
of blood in any systemic
Measurement
Systemic flow (L/min) Pulmonary flow (L/mm) shunt Left-to-right (Limin) Pulmonary artery pressure (mm Hg) Pulmonary artery mean pressure Pulmonary resistance (dynes cm-s see) Oxygen capacity
Minimum
9.5
2.2
is at the extreme
lower limit
mixed
venous
blood
of normal.
oxygen
contents
a wide range so that the arteriovenous
difference
an
between value
average data,
the
149 and 443 ml/min of
250
average
prior to operationwas
so similar
ml/min.
systemic
with Using
blood
flow
4.6 L/min, a normal value.
Pulmonary Blood Flow: artery
In
the oxygen up-
In certain
blood
oxygen
to the systemic
artery
cases
content blood
the was
oxygen
34.0
5.2
17.2
30.9
1.6
12.6
oratory single
82137
f2/4
40/16
62
7
24
24.5
33 13.3
160 18.4
443
149
250
102
93
97
95
68
89
100
94
98
20
2
e
688
96
387
in doing duplicate sample
Neil1 method tients
oxygen contents
on a
of blood by the Van Slyke
and
is about 0.2 vol yO.
in this series,
difference
between
In four pathe arteriovenous oxygen
pulmonary
arterial blood was 0.5 vol
7. or
the data from those patients cluded because they would pulmonary
and
less.
systemic
Arbitrarily,
have not been inhave made the
blood flow values erroneously
high.
With those patients excluded, the pulmonary blood flow varied between 34.0 and 5.2 L/min, the minimum
L
The covered
fell within the limits of 8.1 and 3.1 vol %.
pulmonary 4.6
blood
of less than 93 per cent, which
content that for practical purposes they could be considered identical. The error in this lab-
948
(vol %) Oxygen consumption (ml/min) Femoral blood 02 saturation (%) Pulmonary blood 02 saturation (70) Left atria1 blood 02 saturation (%) (9 cases) Left atria1 pressure (mm Hg) (9 cases) Right ventricular pressure work (kg m/hr) (13 cases)
Average
artery.
oxygen saturation
these Maximum ~-
in
a right
in this group had a systemic
take ranged
Values in 38 Cases of Atria1 Septal Defect
systemic
blood flow it is necessary
the entire group of 38 patients, Preoperative
total pulmo-
and, in a small number
of cases, the right ventricular
No patient
contour,” and other methods.
Defect
nary vascular
of
blood flow by the
be considered
etc.
Septal
flow occurring
in a patient
with
marked elevation of the pulmonary artery pressure in the absence of mitral valve disease. The average value for the group was 17.2 L/min or about four times the systemic blood flow. Left to Right Shunt: The difference between the systemic
and pulmonary
blood flow is the
amount of blood being shunted from left to right at the atria1 level. The range of values was between 1.6 and 30.9 L/min, the average THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Winchell being 12.6 L/min
or about
flow.
three
This
times the sys-
Vascular
Pulmo-
Resistance:
entirely
nary artery pressure depends on the volume flow
correct strated
estimate since it has been well demonby indicator dilution technics that right
through the pulmonary arterial system and the resistance to flow through that system. Resistance is determined by many factors including the cross-sectional area of the pulmonary arteri-
defects
with
an
Pulmonary
blood
to left flow does occur
not
Total
temic
septal
is
and Bashour
in uncomplicated
normal
pressures
atria1
although
the volume of the right to left shunt is ordinarily
olar bed,
not large
posed
content
enough
to
be picked
up by oxygen
studies alone.6
pressure The measurement
Pulmonary Artery Pressure:
of
blood
viscosity,
by the mitral is measured,
impedance
and impedance
valve.
If the
the factor
can be removed
the equation
of heart
catheterization
but in the absence
of regular
seems to be reasonably
accurate
and the figures
left atria1 pressure,
the value computed
at the
obtained correct.
may be considered as approximately In this series, the pressure records
were made
using a strain
gauge
and a direct
writing
recorder. The system was The ba;seline for measuring damped. sures was the midpoint cannot
be located
which terial
pressure
in each patient
but
to be 10 cm anterior
body surface. was derived
The
mean
by electronic
In terms of conventional the pulmonary
ered a wide range,
arinte-
their 75/27,
readings
mm Hg.
Only
coexisting
mitral
pulmonary
artery
as:
is about 250 dynes cm-6
lar resistance
cov-
from a low of 12/4 Eight pa-
being
82/37,
75/38,
disease.
set and the three highest values and 948 dynes cm+
of age, respectively.
In this small sample
level of total pulmonary
72/34,
not related to age or hence to the duration
patients had The average
creased
pulmonary
higher in atria1
value was 160 dynes cm+ normal for an adult.
ure
the
left
atria1
mitral incompetence.
The
mean
pulmonary
of the pressure artery
pressure
curve. in this
reading
between
curred
set, somewhat
below
On nine occasions
it was
pressure.
mean pressure
left
atrium.
In
the
remaining
gradient
nine cases mentioned
1958
patients,
the
across the septal defect
Hg, it is evident that this group of patients
DECEMBER,
in pres-
than a higher mean pressure in the
was from 1 to 10 mm Hg. Left Atria1 Blood Oxygen Saturation:
earlier.
pressure
in a patient who also had In three instances it was
plus or minus 5 mm Hg and since the normal mean pulmonary artery pressure is about 15 mm only mild pulmonary hypertenthe eight patients mentioned
The
as a result of phasic differences
monary artery prer:sure in this laboratory
on the average, sion, excluding
of in-
average
not possible to measure a mean pressure gradient across the atria1 defect, suggesting that flow ocsure rather
had,
The
the was
2 and 20 mm Hg, the highest
occurring
group ranged from 7 to 62 mm Hg with an average value of 24 mm Hg. Since the normal pulis 25/l 0
flow.
resistance
possible to cross the atria1 septal defect and meas-
lieved to occur were not submitted to operation and hence are not included in this report. value is the mean pressure
vascular
blood
Left Atria1 Pressure: do occur
set occurring
hyper-
and 53/16
that probably
pressures
by integration
vascu-
varied from a low of 33 to a high of
ranged
Of more practical
vascuIn
sec.
this series of patients the total pulmonary
septal defect but persons in whom this was be-
obtained
Pressure = ~ Flow
value for total pulmonary
lar resistance
pul-
in patients without associated mitral valve disThose patients were 32, 51, and 19 years ease.
pressure
two of the eight
pressure was 40/16 mm. It should be mentioned
than
The relationship
artery
81/35,
valve
rather
of
is total
were 332,543,
severe pulmonary
70/23,
The normal
measurement
systolic and diastolic
varying
tients had moderately 80/42,
resistance resistance.
Resistance
948 dynes cm+
mm Hg to a high of 82/37 mm Hg. tension,
can be expressed
critically all pres-
gration of the pressure curve. readings,
vascular
arteriolar
of the right atrium which
precisely
may be assumed
to the posterior
pulmonary monary
atria1
of mitral valve
from
time
pressure
im-
left
In the same
above, blood samples were
drawn from the left atrium. The oxygen saturation of the samples fell between 94 and 100 per cent, the average being 98 per cent.
Physiologic
690
Features
Miscellaneous Preoperative Observations: measurements far described
of less importance
of Atria1
pressures
Other
similar
were carried Postoperative
the mean
compared Table
to those done preoperatively
out in 20 patients values
and
to preoperative
after
their
pressure
Hg.
This
time
of operation
converted
surgery.
alterations
findings
were the highest
preoperatively
were
In one case the preop-
erative value of 53/16 mm Hg became 75/30 and
I.
POSTOPERATIVE OBSERVATIONS
Studies
Defect
studied after operation.
than those thus
are also given in Table
Septal
as
changed
patient
had
stance
II. TABLE
of 82/37
mm Hg after
mitral
at the
this was unfortunately A second incompetence.
to mitral
and 80/29
stenosis
and
case had a pressure
are given in
from 30 to 49 mm
mitral
before
surgery.
incompetence
operation In this in-
was present
before
II
Postoperative Values in 20 Cases of Atria1 Septal Defect
Maximum
Measurement
Minimum
Average
Preoperative average
Change in average value
4.6 40/16
+ -
8
+
80
I-
Systemic flow (L/mm) Pulmonary artery pressure (mm Hg) Pulmonary artery, mean pressure resistance (dynes Pulmonary cm -5 SW) Oxygen capacity (vol $Zo) Oxygen consumption (ml/min) Femoral blood 0s saturation (%) Pulmonary blood 0s saturation (%) A-V 02 difference (vol ‘%) Right ventricular pressure work (kg m/hr) (13 cases)
Systemic Flow,
7/l
6.1 26/10
49 687
3 49
16 240
24 160
an anomalous
pulmonary
15.3 163 92 71
17.8 213 98 79
18.4 250 97 89
-
0.6 37
+ -
1 10
65 213
25 39
3.7 98
52 387
15 -289
and Left
been
to
was a residual through
vein that entered
the
atrium at its junction with the superior cava. This had not been discovered at
the time of operation corrected.
anomalous
and consequently
The
catheter
had not
entered
the
vein at the time of the postoperative
catheterization. was calculated
15 14/6
22.2 313 103 87
left to right shunt found, this occurring right vena
2.8
-I
Pulmonary Flow,
Right Shunt: In only one patient
10 1 80/29
The residual shunt in this case to be 2.1 L/min as compared to
8.7 L/min preoperatively. For the entire group, the systemic flow was found to be 6.1 L/min, a value 1.5 L/min larger than preoperatively. Pulmonary Artery Pressure: The pulmonary artery pressure was found to average 26/10 mm Hg postoperatively with an average mean pulmonary artery pressure of 16 mm Hg. Three of the eight patients previously mentioned whose
the operation eration.
and was not corrected
In a third
patient
by the op-
the initial
pulmo-
nary artery pressure was 72/34 mm Hg. It was not possible to enter the pulmonary artery at the second heart tricular Hg.
catheterization
pressure
but the right ven-
after operation
was 28/4 mm
In this case the original pulmonary
hyper-
tension seems to have been caused solely by the increased
pulmonary
tomic change
blood
flow without
in the pulmonary
arteriolar
anabed.
A functional decrease in the size of the pulmonary arterioles cannot, of course, be excluded. One other pressure change noted in the preoperative material and not fully understood until the postoperative studies had been done was related to the presence of a systolic gradient across the pulmonary valve. At first glance these data suggested that mild pulmonary stenosis was also present since the systolic gradient in THE
AMERICAN
JOURNAL
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CARDIOLOGY
Winchell Follow-
six cases ranged from 12 to 28 mm Hg. ing obliteration
of the left to right shunt, no sys-
tolic gradient indicating
higher than 5 mm Hg was found,
that organic
not
been
call
this
present. “relative”
upon increased ally normal
pulmonary
reasonable to stenosis based
volume flow across an anatomic-
pulmonary
valve.
no case of true pulmonary This
stenosis had
It seemed pulmonary
phenomenon
In this series,
stenosis was found.
is probably
responsible
for
other cases reported in the literature as atria1 septal defect with pulmonary stenosis in which gradients
across the pulmonary
valve as low as
15 mm Hg were measured.’ in the total pulmonary
ance was seen following ranged
operation.
vascular resistThe values
from 49 to 687 dynes cm-5
average
value
change
of 240
was related
where Q = pulmonary blood flow in L/min and R = right ventricular mean systolic pressure in mm Hg.9
Preoperatively, ventricular following m/hr.
dynes
set with an This sec.
crne6
not so much
to changes
that previously
reported
vascular tor
resistance,
has been shown that increasing companied
the pOZ is ac-
by a drop in pulmonary
sistance while a decrease and postoperative oxygen
respectively)
The
saturation
changes
defect
physiologically
artery
(89 and 79 per cent,
imply similar
with an atria1 septal
re-
preoperative
values for pulmonary
and would fit wit11 this concept. similar
vascular
in the pOZ is followed
by a rise in the resistance.8 blood
blood since it
in the pOZ The
patient
would seem to be
in some
respects
to a
person breathing high oxygen concentrations. Right Ventricular Pressure Work: One of the earlier
reports
on the dynamics
defect in the adult included right
ventricular
reported, averaged
the
factors
right
ventricular
value of 105 kg m/hr.
jects.
pressure
of kinetic
work
and
ignored
of work
pressure
work
to a theoretiIt was also
out that these calculations
from turbulent fl~vr.~ The right ventricular culated
measurement of the In the series
work.
361 kg m/hr as compared
cal normal pointed
pressure
of atria1 septal
the
resulting
work was cal-
both before and after surgery in 13 subThe
relationship
of pressure,
flow, and
work is as follows : Right ventricular pressure work = 60 Q times R (0.0135)
DECEMBER,1958
above
was the marked
fac-
reduction
blood flow rather than a sizeable The right ventricular mean
systolic
pressure
dropped
only from
mm Hg while the decrease
28 to 17
in right ventricular
pressure work was proportionately
much larger.
DISCUSSION
in
to the oxygen
artery
and is definitely
change in pressure.
in atria1 septal
is also related
for right
the major contributing
to this change
that
in the pulmonary
value
normal while the postoperative value is well As with total pulmonary within normal limits.
outline
this change
average
surgery the average value was 98 kg The initial value corresponds closely to
pressure but rather to the marked change in pulIt is interesting to consider monary blood flow. tension
the
pressure work was 387 kg m/hr while
in pulmonary
Total Pulmonary Vascular Resistance: A regular increase
691
and Bashour
The
clude
data obtained the
in this group
major
enormous
physiologic
defect
in the adult,
increases
pressure,
which
in pulmonary
flow, only mild to moderate nary artery
of patients
abnormalities
increases
in-
blood
in pulmo-
lower than normal
values
for total pulmonary vascular resistance, and normal systemic arterial blood oxygen saturation.
These
findings
are
other data in the literature exceptions
agreement
although
with
individual
to the general hemodynamic pattern The studies were not done in such
do occur.l” a manner
in
that the presence
of small right to left
shunts despite normal pulmonary artery pressure could be either confirmed or denied but in any event enough
such
shunts,
if present,
were
to alter the systemic arterial
gen saturation. fect brought anticipate
Closure of the atria1 septal de-
about
the changes
such as reduction
flow to normal,
reduction
pressure if it was initially of the total
not large blood oxy-
pulmonary
that one would
of pulmonary of pulmonary
elevated, vascular
blood artery
and a return resistance
to-
wards normal. Changes in the functions of lesser importance, as enumerated in Tables I and II, were not of real significance and do not merit further discussion here. Genesis of Pulmonary Hypertension: One cluestion of major importance concerns the genesis of pulmonary hypertension in atria1 septal defect
Physiologic
692 since major elevations
of pulmonary
sure
make
repair
lung
vascular
mendous
surgical bed
increases
Features artery pres-
impossible.
ordinarily
can
in blood
of Atria1
The
accept
tre-
flow, as has been
Septal
competence
Defect was present
artery
pressure remained
tive level.
The
after operation
pulmonary
is only slightly eleAll of the factors vated in atria1 septal defect.
degree the part played
contributing
to the development
elevated.
hypertension
in rare cases have not been defined.
That
pressure
long standing
left to right shunts may be
complicated
by the development
hypertension
is suggested
and can be produced circumstances.”
of pulmonary
of pulmonary
by clinical
in the dog under
Anatomic
alteration
media and the intima of the pulmonary can be seen in the experimental
averages
arterioles This hyper-
in this group with the
Claude
tioned.
medicine
nary
hypertension
explanation is that
Bernard
physiology,
to error.
monary
a residual
hypertension.
biological
character
not be ruled out with certainty perience
can-
but personal
ex-
with atria1 defect in children would sug-
gest that this is not a likely explanation. Probably a common contributing pulmonary
hypertension
septal defect
of this combination
and
of phenomena,
in physiology
gives only apparent
com-
By destroying
and
medicine
accuracy
to
of mitral
valve
The in-
of abnormalities
is
the
the use of usually
to the results.“13
SUMMARY (1)
Thirty-eight
adult
patients
with
atria1
septal defect have been studied before operation, and (2)
20 have been restudied postoperatively. Of the group, two had significant mitral
valve disease and two were of the ostium cause
in the adult with atria1
is the coexistence
disease, either stenosis or incompetence. cidence
fetal pul-
a possibility
complexity
definite
one with another.
it has not developed
Such
phenom-
being
to support
sev-
to physiological
which
for the pulmo-
of the normal
are doubtless
arterioles
their
in
obstacle
calculation
prevents
which,
but the greatest the excessive
parable
thus:
so to speak,
ena is still, at bottom,
but
it
of mathemat-
leads,
There
for this;
over the years but has been present since birth, representing
expressed
to applying
averages
such an idea. Another possible
blood flow measurements,
arteriolar raises the
resistance
there seems to be no other evidence
the total
is the use of averages
and
eral reasons
of pulmonary
that
of the basic ob-
very frequent application
necessarily
pressure, and a normal lung
in vascular
for the reasons
especially
highest pressure was 19 years old, had a normal
of “spasm”
been
would not warrant precise statistical manipulaEven the use of averages may be questions.
pulmonary
and hence an increase
not
servations,
the
ics to biology
question
have
of these data other than
of
with atria1 septal defect with pulmonary
biopsy, with no evidence of pulmonary Such a finding immediately
methods
pressure
certain
animal.
sclerosis.
to some
valve dis-
artery
sample is small and the accuracy
“Another
capillary
the pulmonary
statistical
is not always the course of events in the human tension since the patient
pressure
by the mitral
used in the evaluation simple
experience
capillary
was 19 mm Hg, indicating
ease in keeping Finally,
at the high preopera-
pulmonary
shown in this series of cases, and as a rule the artery
before surgery and de-
spite closure of the septal defect, the pulmonary
mum type although from the secundum namic findings. (3)
The
operation
major were:
pri-
they could not be separated defects
by their
physiologic (a)
marked
hemody-
findings increase
before in pul-
given as about 6 per cent12 and played a signifiIn cant role in two of the patients in this series. one patient who had mitral stenosis, mitral incompetence was produced at operation and the mean pulmonary artery pressure rose from 30
monary blood flow; (b) normal systemic blood flow; (c) mild elevation of pulmonary artery pressure ; (d) lower than normal total pulmonary vascular resistance; (e) increased right ventricular pressure work; (f) normal systemic
to 49 mm despite closure of the atria1 defect. The net result, however, was a reduction of the right ventricular pressure work from 604 to
arterial
213 kg m/hr, so that the patient functionally.
In
the
second
was improved
case,
mitral
in-
blood oxygen saturation.
(4) Surgical correction of the atria1 septal defect resulted in a reversion of the physiologic abnormalities towards or to normal. (5) “Relative” pulmonary stenosis may be THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Winchell
and Bashour
present in the face of marked increases in the pulmonary blood flow. (6) The genesis of pulmonary certain
cases is not totally
be related to : (a) pulmonary (b)
residual
fetal
hypertension
understood arteriolar
pulmonary
(c) associated mitral valve disease; of the pulmonary
in
but may sclerosis;
hypertension; (d) “spasm”
arterioles.
1. LEWIS, F. J., WINCHELL, P., and BASHOUR, F.: The open repair of atria1 septal defects. J.A.M.A. 165: 922, 1957. 2. STOW, R. W.: Systematic errors in flow determinations by the Fick method. Minnesota Med. 37: 30, 1954. 3. DEXTER, L., HAYIYES,F. W., BUR~ELL, C. S., EPPINCER,E. C., SAGERSON,R. P., and EVANS, J. M.: Studies of congenital heart disease. II. The pressure and oxygen content of blood in the right auricle, right ventricle, and pulmonary artery in control patients, with observations on the oxygen saturation and the source of pulmonary “capillary” blood. J. Clin. Invest. 26: 554, 1947. 4. SHEPPARD, C. W. : Mathematical considerations of indicator dilution techniques. Minnesota Med. 37: 93, 1954. 5. WARNER, H. R.: Quantitation of stroke volume changes in man from the central pressure pulse. Minnesota Med. 37: 111, 1954.
DECEMBER,1958
6. SWAN, H. J. C., BURCHELL,H., and WOOD, E. H.: The presence of venoarterial shunts in patients with interatrial communications. Circulation 10 : 705, 1954. 7. RUDOLPH, A. M., NADAS, A, S., and GOODALE, W. T.: Intracardiac left to right shunt with pulmanic stenosis. Am. Heart .I. 48: 808, 1954. 8. BURCHELL,H., SWAN, H. J. C., and WOOD, E. H.: Demonstration of differential effects on pulmonary and systemic arterial pressure by variation of oxygen content of inspired air in patients with patent ductus arteriosus and pulmonary hypertension. Circulation 8: 681; 1953. 9. CHAPMAN, C. B. and FRASER, R. S.: Clinical and hemodynamic features of uncomplicated interatria1 defect in adults. Am. Heart J. 46: 3, 1953. 10. BLOUNT, S. G., JR., SWAN, H., GENSINI, G., and Circulation MCCORD, M. : Atria1 septal defect. 9: 801, 1954. 11. FERGUSON,D. J. and VARCO, R. L. : The relation of blood pressure and flow to the development and regression of experimentally induced pulmonary arteriosclerosis. Circulation Res. 8 : 152, 1955. 12. NADAS, A. S. and ALIMURING,M. M.: Apical diastolic murmurs in congenital heart disease; rarity of Lutembacher’s syndrome. Am. Heart J. 43: 691, 1952. 13. BERNARD, C. : An Introduction to the Study of Experimental Medicine (trans. by Henry C. Greene). Dover Publications, Inc., New York, 1957, p. 134.
T
HE APPLICATION of hypothermia cardiac
surgical problems
the repair
of atria1 septal
this group and in the cases to be presented
to certain
cator dilution
has made possible
defects
Minnesota
employed.
in the adult
indi-
curves have not been extensively
Recently,
indicator
dilution
curves
with an operative mortality of less than 10 per Using the hypothermia technic, open cent.’
utilizing Renografin+ or human serum albumin made radioactive with 1131 as a tracer isotope
atria1 septal defect repair
have been included
a group
of 38 adult
has been achieved
patients.
These
in
in the routine
thus far have not, for practical
patients
ranged in age from 16 to 61 years and of the to-
great value.
tal group, 20 have been restudied
samples taken at the time of heart
graphic,
was examined
or deny
atria1 septal
defect
and
the
Manometric
but
analysis of the blood catheteriza-
tion has been carried out.
operation. Each patient to confirm
following
studies
purposes, been of
the
by roentgen,
cathseterization
It should
preoperatively
clinical
diagnosis
at the outset
in either
Only
that
error is involved in the application
of the Fick law to the calculation
electrocardio-
methods.
be emphasized
considerable
of
the systemic
and especially
of volume flow
or pulmonary
circulation
so in the presence of large left-to-
patients in whom the diagnosis was confirmed at The data operation are included in this report.
right shunts.2
thus are not confused
blood within the right side of the heart is not per-
by the inclusion
of mal-
that may closely imitate
atria1 septal
fect,
defect, such as partial anomalous venous return to the right atrium,
pulmonary aortic sinus
the right ventricle
formations
aneurysm
with rupture
ventricular petence,
septal
defect
into
the right
atrium,
with tricuspid
incorn:
or atrioventricularis
communis
especially
It is well known that mixing
therefore
in the right
but also in artery.
It is ar-
unlikely that any single pulmonary
tery blood sample nous sample. is involved
defects.
atrium
and pulmonary represents
a true mixed
The same type of sampling
in drawing
veerror
blood from any systemic
Of the total group, only two of the atria1 defects
artery
were of the ostium primum variety and in only two instances was significant mitral valvular
smaller than in the pulmonary circuit. In calculating systemic blood flow in the pres-
disease also present.
ence of a left-to-right
used in studying
the variation
the venous sample
METHODS The methods
although
of
in such samples is
shunt, it is necessary to use in the chamber
proximal
to
the shunt as the mixed venous sample. In the case of atria1 septal defect, this would be either
these patients
vena cava or, if possible, an average value from both venae cavae. Since volume flow and blood
have been the standard procedures. Angiocardiography has not been used regularly in
* From the Departments of Medicine, University of Minnesota, Minneapolis, and American University, Beirut, Lebanon. t E. R. Squibb & Co. DECEMBER,
1958
687
Physiologic
688 oxygen
content
Features
of Atria1
in the two venae cavae are not
identical,
average values may involve considerProbably the errors inherent in error.3
able
measuring
oxygen uptake are inconsequential
compared
to those related
to blood
as
sampling.
All of these values are used in the calculation both systemic and pulmonary Fick principle
and obviously
computations
must
only. cal
as estimates
It is only fair to point out that any clinimethod
from
the results of such
for calculating
perfect
and
that
blood
flow is far
fundamental
exist relative to indicator
problems
dilution,4 arterial
pulse
PREOPERATIVE OBSERVATIONS Measurements pulmonary
have been made of systemic and
blood flow, pulmonary
sure, systemic arterial saturation,
Volume
arterial
pres-
oxygen uptake,
flow in both circuits, resistance,
been calculated. in Table
pressure work have
The pertinent
data are given
I.
Systemic Flow:
In order to calculate
TABLE 1
to know the oxygen up-
take, the oxygen content
of a mixed venous sam-
ple proximal
to the shunt, and the oxygen con-
tent of the pulmonary
venous blood which,
the normally
saturated
patient
to left shunt,
is assumed
oxygen content
without
-
to be the same as the
of blood in any systemic
Measurement
Systemic flow (L/min) Pulmonary flow (L/mm) shunt Left-to-right (Limin) Pulmonary artery pressure (mm Hg) Pulmonary artery mean pressure Pulmonary resistance (dynes cm-s see) Oxygen capacity
Minimum
9.5
2.2
is at the extreme
lower limit
mixed
venous
blood
of normal.
oxygen
contents
a wide range so that the arteriovenous
difference
an
between value
average data,
the
149 and 443 ml/min of
250
average
prior to operationwas
so similar
ml/min.
systemic
with Using
blood
flow
4.6 L/min, a normal value.
Pulmonary Blood Flow: artery
In
the oxygen up-
In certain
blood
oxygen
to the systemic
artery
cases
content blood
the was
oxygen
34.0
5.2
17.2
30.9
1.6
12.6
oratory single
82137
f2/4
40/16
62
7
24
24.5
33 13.3
160 18.4
443
149
250
102
93
97
95
68
89
100
94
98
20
2
e
688
96
387
in doing duplicate sample
Neil1 method tients
oxygen contents
on a
of blood by the Van Slyke
and
is about 0.2 vol yO.
in this series,
difference
between
In four pathe arteriovenous oxygen
pulmonary
arterial blood was 0.5 vol
7. or
the data from those patients cluded because they would pulmonary
and
less.
systemic
Arbitrarily,
have not been inhave made the
blood flow values erroneously
high.
With those patients excluded, the pulmonary blood flow varied between 34.0 and 5.2 L/min, the minimum
L
The covered
fell within the limits of 8.1 and 3.1 vol %.
pulmonary 4.6
blood
of less than 93 per cent, which
content that for practical purposes they could be considered identical. The error in this lab-
948
(vol %) Oxygen consumption (ml/min) Femoral blood 02 saturation (%) Pulmonary blood 02 saturation (70) Left atria1 blood 02 saturation (%) (9 cases) Left atria1 pressure (mm Hg) (9 cases) Right ventricular pressure work (kg m/hr) (13 cases)
Average
artery.
oxygen saturation
these Maximum ~-
in
a right
in this group had a systemic
take ranged
Values in 38 Cases of Atria1 Septal Defect
systemic
blood flow it is necessary
the entire group of 38 patients, Preoperative
total pulmo-
and, in a small number
of cases, the right ventricular
No patient
contour,” and other methods.
Defect
nary vascular
of
blood flow by the
be considered
etc.
Septal
flow occurring
in a patient
with
marked elevation of the pulmonary artery pressure in the absence of mitral valve disease. The average value for the group was 17.2 L/min or about four times the systemic blood flow. Left to Right Shunt: The difference between the systemic
and pulmonary
blood flow is the
amount of blood being shunted from left to right at the atria1 level. The range of values was between 1.6 and 30.9 L/min, the average THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Winchell being 12.6 L/min
or about
flow.
three
This
times the sys-
Vascular
Pulmo-
Resistance:
entirely
nary artery pressure depends on the volume flow
correct strated
estimate since it has been well demonby indicator dilution technics that right
through the pulmonary arterial system and the resistance to flow through that system. Resistance is determined by many factors including the cross-sectional area of the pulmonary arteri-
defects
with
an
Pulmonary
blood
to left flow does occur
not
Total
temic
septal
is
and Bashour
in uncomplicated
normal
pressures
atria1
although
the volume of the right to left shunt is ordinarily
olar bed,
not large
posed
content
enough
to
be picked
up by oxygen
studies alone.6
pressure The measurement
Pulmonary Artery Pressure:
of
blood
viscosity,
by the mitral is measured,
impedance
and impedance
valve.
If the
the factor
can be removed
the equation
of heart
catheterization
but in the absence
of regular
seems to be reasonably
accurate
and the figures
left atria1 pressure,
the value computed
at the
obtained correct.
may be considered as approximately In this series, the pressure records
were made
using a strain
gauge
and a direct
writing
recorder. The system was The ba;seline for measuring damped. sures was the midpoint cannot
be located
which terial
pressure
in each patient
but
to be 10 cm anterior
body surface. was derived
The
mean
by electronic
In terms of conventional the pulmonary
ered a wide range,
arinte-
their 75/27,
readings
mm Hg.
Only
coexisting
mitral
pulmonary
artery
as:
is about 250 dynes cm-6
lar resistance
cov-
from a low of 12/4 Eight pa-
being
82/37,
75/38,
disease.
set and the three highest values and 948 dynes cm+
of age, respectively.
In this small sample
level of total pulmonary
72/34,
not related to age or hence to the duration
patients had The average
creased
pulmonary
higher in atria1
value was 160 dynes cm+ normal for an adult.
ure
the
left
atria1
mitral incompetence.
The
mean
pulmonary
of the pressure artery
pressure
curve. in this
reading
between
curred
set, somewhat
below
On nine occasions
it was
pressure.
mean pressure
left
atrium.
In
the
remaining
gradient
nine cases mentioned
1958
patients,
the
across the septal defect
Hg, it is evident that this group of patients
DECEMBER,
in pres-
than a higher mean pressure in the
was from 1 to 10 mm Hg. Left Atria1 Blood Oxygen Saturation:
earlier.
pressure
in a patient who also had In three instances it was
plus or minus 5 mm Hg and since the normal mean pulmonary artery pressure is about 15 mm only mild pulmonary hypertenthe eight patients mentioned
The
as a result of phasic differences
monary artery prer:sure in this laboratory
on the average, sion, excluding
of in-
average
not possible to measure a mean pressure gradient across the atria1 defect, suggesting that flow ocsure rather
had,
The
the was
2 and 20 mm Hg, the highest
occurring
group ranged from 7 to 62 mm Hg with an average value of 24 mm Hg. Since the normal pulis 25/l 0
flow.
resistance
possible to cross the atria1 septal defect and meas-
lieved to occur were not submitted to operation and hence are not included in this report. value is the mean pressure
vascular
blood
Left Atria1 Pressure: do occur
set occurring
hyper-
and 53/16
that probably
pressures
by integration
vascu-
varied from a low of 33 to a high of
ranged
Of more practical
vascuIn
sec.
this series of patients the total pulmonary
septal defect but persons in whom this was be-
obtained
Pressure = ~ Flow
value for total pulmonary
lar resistance
pul-
in patients without associated mitral valve disThose patients were 32, 51, and 19 years ease.
pressure
two of the eight
pressure was 40/16 mm. It should be mentioned
than
The relationship
artery
81/35,
valve
rather
of
is total
were 332,543,
severe pulmonary
70/23,
The normal
measurement
systolic and diastolic
varying
tients had moderately 80/42,
resistance resistance.
Resistance
948 dynes cm+
mm Hg to a high of 82/37 mm Hg. tension,
can be expressed
critically all pres-
gration of the pressure curve. readings,
vascular
arteriolar
of the right atrium which
precisely
may be assumed
to the posterior
pulmonary monary
atria1
of mitral valve
from
time
pressure
im-
left
In the same
above, blood samples were
drawn from the left atrium. The oxygen saturation of the samples fell between 94 and 100 per cent, the average being 98 per cent.
Physiologic
690
Features
Miscellaneous Preoperative Observations: measurements far described
of less importance
of Atria1
pressures
Other
similar
were carried Postoperative
the mean
compared Table
to those done preoperatively
out in 20 patients values
and
to preoperative
after
their
pressure
Hg.
This
time
of operation
converted
surgery.
alterations
findings
were the highest
preoperatively
were
In one case the preop-
erative value of 53/16 mm Hg became 75/30 and
I.
POSTOPERATIVE OBSERVATIONS
Studies
Defect
studied after operation.
than those thus
are also given in Table
Septal
as
changed
patient
had
stance
II. TABLE
of 82/37
mm Hg after
mitral
at the
this was unfortunately A second incompetence.
to mitral
and 80/29
stenosis
and
case had a pressure
are given in
from 30 to 49 mm
mitral
before
surgery.
incompetence
operation In this in-
was present
before
II
Postoperative Values in 20 Cases of Atria1 Septal Defect
Maximum
Measurement
Minimum
Average
Preoperative average
Change in average value
4.6 40/16
+ -
8
+
80
I-
Systemic flow (L/mm) Pulmonary artery pressure (mm Hg) Pulmonary artery, mean pressure resistance (dynes Pulmonary cm -5 SW) Oxygen capacity (vol $Zo) Oxygen consumption (ml/min) Femoral blood 0s saturation (%) Pulmonary blood 0s saturation (%) A-V 02 difference (vol ‘%) Right ventricular pressure work (kg m/hr) (13 cases)
Systemic Flow,
7/l
6.1 26/10
49 687
3 49
16 240
24 160
an anomalous
pulmonary
15.3 163 92 71
17.8 213 98 79
18.4 250 97 89
-
0.6 37
+ -
1 10
65 213
25 39
3.7 98
52 387
15 -289
and Left
been
to
was a residual through
vein that entered
the
atrium at its junction with the superior cava. This had not been discovered at
the time of operation corrected.
anomalous
and consequently
The
catheter
had not
entered
the
vein at the time of the postoperative
catheterization. was calculated
15 14/6
22.2 313 103 87
left to right shunt found, this occurring right vena
2.8
-I
Pulmonary Flow,
Right Shunt: In only one patient
10 1 80/29
The residual shunt in this case to be 2.1 L/min as compared to
8.7 L/min preoperatively. For the entire group, the systemic flow was found to be 6.1 L/min, a value 1.5 L/min larger than preoperatively. Pulmonary Artery Pressure: The pulmonary artery pressure was found to average 26/10 mm Hg postoperatively with an average mean pulmonary artery pressure of 16 mm Hg. Three of the eight patients previously mentioned whose
the operation eration.
and was not corrected
In a third
patient
by the op-
the initial
pulmo-
nary artery pressure was 72/34 mm Hg. It was not possible to enter the pulmonary artery at the second heart tricular Hg.
catheterization
pressure
but the right ven-
after operation
was 28/4 mm
In this case the original pulmonary
hyper-
tension seems to have been caused solely by the increased
pulmonary
tomic change
blood
flow without
in the pulmonary
arteriolar
anabed.
A functional decrease in the size of the pulmonary arterioles cannot, of course, be excluded. One other pressure change noted in the preoperative material and not fully understood until the postoperative studies had been done was related to the presence of a systolic gradient across the pulmonary valve. At first glance these data suggested that mild pulmonary stenosis was also present since the systolic gradient in THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Winchell Follow-
six cases ranged from 12 to 28 mm Hg. ing obliteration
of the left to right shunt, no sys-
tolic gradient indicating
higher than 5 mm Hg was found,
that organic
not
been
call
this
present. “relative”
upon increased ally normal
pulmonary
reasonable to stenosis based
volume flow across an anatomic-
pulmonary
valve.
no case of true pulmonary This
stenosis had
It seemed pulmonary
phenomenon
In this series,
stenosis was found.
is probably
responsible
for
other cases reported in the literature as atria1 septal defect with pulmonary stenosis in which gradients
across the pulmonary
valve as low as
15 mm Hg were measured.’ in the total pulmonary
ance was seen following ranged
operation.
vascular resistThe values
from 49 to 687 dynes cm-5
average
value
change
of 240
was related
where Q = pulmonary blood flow in L/min and R = right ventricular mean systolic pressure in mm Hg.9
Preoperatively, ventricular following m/hr.
dynes
set with an This sec.
crne6
not so much
to changes
that previously
reported
vascular tor
resistance,
has been shown that increasing companied
the pOZ is ac-
by a drop in pulmonary
sistance while a decrease and postoperative oxygen
respectively)
The
saturation
changes
defect
physiologically
artery
(89 and 79 per cent,
imply similar
with an atria1 septal
re-
preoperative
values for pulmonary
and would fit wit11 this concept. similar
vascular
in the pOZ is followed
by a rise in the resistance.8 blood
blood since it
in the pOZ The
patient
would seem to be
in some
respects
to a
person breathing high oxygen concentrations. Right Ventricular Pressure Work: One of the earlier
reports
on the dynamics
defect in the adult included right
ventricular
reported, averaged
the
factors
right
ventricular
value of 105 kg m/hr.
jects.
pressure
of kinetic
work
and
ignored
of work
pressure
work
to a theoretiIt was also
out that these calculations
from turbulent fl~vr.~ The right ventricular culated
measurement of the In the series
work.
361 kg m/hr as compared
cal normal pointed
pressure
of atria1 septal
the
resulting
work was cal-
both before and after surgery in 13 subThe
relationship
of pressure,
flow, and
work is as follows : Right ventricular pressure work = 60 Q times R (0.0135)
DECEMBER,1958
above
was the marked
fac-
reduction
blood flow rather than a sizeable The right ventricular mean
systolic
pressure
dropped
only from
mm Hg while the decrease
28 to 17
in right ventricular
pressure work was proportionately
much larger.
DISCUSSION
in
to the oxygen
artery
and is definitely
change in pressure.
in atria1 septal
is also related
for right
the major contributing
to this change
that
in the pulmonary
value
normal while the postoperative value is well As with total pulmonary within normal limits.
outline
this change
average
surgery the average value was 98 kg The initial value corresponds closely to
pressure but rather to the marked change in pulIt is interesting to consider monary blood flow. tension
the
pressure work was 387 kg m/hr while
in pulmonary
Total Pulmonary Vascular Resistance: A regular increase
691
and Bashour
The
clude
data obtained the
in this group
major
enormous
physiologic
defect
in the adult,
increases
pressure,
which
in pulmonary
flow, only mild to moderate nary artery
of patients
abnormalities
increases
in-
blood
in pulmo-
lower than normal
values
for total pulmonary vascular resistance, and normal systemic arterial blood oxygen saturation.
These
findings
are
other data in the literature exceptions
agreement
although
with
individual
to the general hemodynamic pattern The studies were not done in such
do occur.l” a manner
in
that the presence
of small right to left
shunts despite normal pulmonary artery pressure could be either confirmed or denied but in any event enough
such
shunts,
if present,
were
to alter the systemic arterial
gen saturation. fect brought anticipate
Closure of the atria1 septal de-
about
the changes
such as reduction
flow to normal,
reduction
pressure if it was initially of the total
not large blood oxy-
pulmonary
that one would
of pulmonary of pulmonary
elevated, vascular
blood artery
and a return resistance
to-
wards normal. Changes in the functions of lesser importance, as enumerated in Tables I and II, were not of real significance and do not merit further discussion here. Genesis of Pulmonary Hypertension: One cluestion of major importance concerns the genesis of pulmonary hypertension in atria1 septal defect
Physiologic
692 since major elevations
of pulmonary
sure
make
repair
lung
vascular
mendous
surgical bed
increases
Features artery pres-
impossible.
ordinarily
can
in blood
of Atria1
The
accept
tre-
flow, as has been
Septal
competence
Defect was present
artery
pressure remained
tive level.
The
after operation
pulmonary
is only slightly eleAll of the factors vated in atria1 septal defect.
degree the part played
contributing
to the development
elevated.
hypertension
in rare cases have not been defined.
That
pressure
long standing
left to right shunts may be
complicated
by the development
hypertension
is suggested
and can be produced circumstances.”
of pulmonary
of pulmonary
by clinical
in the dog under
Anatomic
alteration
media and the intima of the pulmonary can be seen in the experimental
averages
arterioles This hyper-
in this group with the
Claude
tioned.
medicine
nary
hypertension
explanation is that
Bernard
physiology,
to error.
monary
a residual
hypertension.
biological
character
not be ruled out with certainty perience
can-
but personal
ex-
with atria1 defect in children would sug-
gest that this is not a likely explanation. Probably a common contributing pulmonary
hypertension
septal defect
of this combination
and
of phenomena,
in physiology
gives only apparent
com-
By destroying
and
medicine
accuracy
to
of mitral
valve
The in-
of abnormalities
is
the
the use of usually
to the results.“13
SUMMARY (1)
Thirty-eight
adult
patients
with
atria1
septal defect have been studied before operation, and (2)
20 have been restudied postoperatively. Of the group, two had significant mitral
valve disease and two were of the ostium cause
in the adult with atria1
is the coexistence
disease, either stenosis or incompetence. cidence
fetal pul-
a possibility
complexity
definite
one with another.
it has not developed
Such
phenom-
being
to support
sev-
to physiological
which
for the pulmo-
of the normal
are doubtless
arterioles
their
in
obstacle
calculation
prevents
which,
but the greatest the excessive
parable
thus:
so to speak,
ena is still, at bottom,
but
it
of mathemat-
leads,
There
for this;
over the years but has been present since birth, representing
expressed
to applying
averages
such an idea. Another possible
blood flow measurements,
arteriolar raises the
resistance
there seems to be no other evidence
the total
is the use of averages
and
eral reasons
of pulmonary
that
of the basic ob-
very frequent application
necessarily
pressure, and a normal lung
in vascular
for the reasons
especially
highest pressure was 19 years old, had a normal
of “spasm”
been
would not warrant precise statistical manipulaEven the use of averages may be questions.
pulmonary
and hence an increase
not
servations,
the
ics to biology
question
have
of these data other than
of
with atria1 septal defect with pulmonary
biopsy, with no evidence of pulmonary Such a finding immediately
methods
pressure
certain
animal.
sclerosis.
to some
valve dis-
artery
sample is small and the accuracy
“Another
capillary
the pulmonary
statistical
is not always the course of events in the human tension since the patient
pressure
by the mitral
used in the evaluation simple
experience
capillary
was 19 mm Hg, indicating
ease in keeping Finally,
at the high preopera-
pulmonary
shown in this series of cases, and as a rule the artery
before surgery and de-
spite closure of the septal defect, the pulmonary
mum type although from the secundum namic findings. (3)
The
operation
major were:
pri-
they could not be separated defects
by their
physiologic (a)
marked
hemody-
findings increase
before in pul-
given as about 6 per cent12 and played a signifiIn cant role in two of the patients in this series. one patient who had mitral stenosis, mitral incompetence was produced at operation and the mean pulmonary artery pressure rose from 30
monary blood flow; (b) normal systemic blood flow; (c) mild elevation of pulmonary artery pressure ; (d) lower than normal total pulmonary vascular resistance; (e) increased right ventricular pressure work; (f) normal systemic
to 49 mm despite closure of the atria1 defect. The net result, however, was a reduction of the right ventricular pressure work from 604 to
arterial
213 kg m/hr, so that the patient functionally.
In
the
second
was improved
case,
mitral
in-
blood oxygen saturation.
(4) Surgical correction of the atria1 septal defect resulted in a reversion of the physiologic abnormalities towards or to normal. (5) “Relative” pulmonary stenosis may be THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Winchell
and Bashour
present in the face of marked increases in the pulmonary blood flow. (6) The genesis of pulmonary certain
cases is not totally
be related to : (a) pulmonary (b)
residual
fetal
hypertension
understood arteriolar
pulmonary
(c) associated mitral valve disease; of the pulmonary
in
but may sclerosis;
hypertension; (d) “spasm”
arterioles.
1. LEWIS, F. J., WINCHELL, P., and BASHOUR, F.: The open repair of atria1 septal defects. J.A.M.A. 165: 922, 1957. 2. STOW, R. W.: Systematic errors in flow determinations by the Fick method. Minnesota Med. 37: 30, 1954. 3. DEXTER, L., HAYIYES,F. W., BUR~ELL, C. S., EPPINCER,E. C., SAGERSON,R. P., and EVANS, J. M.: Studies of congenital heart disease. II. The pressure and oxygen content of blood in the right auricle, right ventricle, and pulmonary artery in control patients, with observations on the oxygen saturation and the source of pulmonary “capillary” blood. J. Clin. Invest. 26: 554, 1947. 4. SHEPPARD, C. W. : Mathematical considerations of indicator dilution techniques. Minnesota Med. 37: 93, 1954. 5. WARNER, H. R.: Quantitation of stroke volume changes in man from the central pressure pulse. Minnesota Med. 37: 111, 1954.
DECEMBER,1958
6. SWAN, H. J. C., BURCHELL,H., and WOOD, E. H.: The presence of venoarterial shunts in patients with interatrial communications. Circulation 10 : 705, 1954. 7. RUDOLPH, A. M., NADAS, A, S., and GOODALE, W. T.: Intracardiac left to right shunt with pulmanic stenosis. Am. Heart .I. 48: 808, 1954. 8. BURCHELL,H., SWAN, H. J. C., and WOOD, E. H.: Demonstration of differential effects on pulmonary and systemic arterial pressure by variation of oxygen content of inspired air in patients with patent ductus arteriosus and pulmonary hypertension. Circulation 8: 681; 1953. 9. CHAPMAN, C. B. and FRASER, R. S.: Clinical and hemodynamic features of uncomplicated interatria1 defect in adults. Am. Heart J. 46: 3, 1953. 10. BLOUNT, S. G., JR., SWAN, H., GENSINI, G., and Circulation MCCORD, M. : Atria1 septal defect. 9: 801, 1954. 11. FERGUSON,D. J. and VARCO, R. L. : The relation of blood pressure and flow to the development and regression of experimentally induced pulmonary arteriosclerosis. Circulation Res. 8 : 152, 1955. 12. NADAS, A. S. and ALIMURING,M. M.: Apical diastolic murmurs in congenital heart disease; rarity of Lutembacher’s syndrome. Am. Heart J. 43: 691, 1952. 13. BERNARD, C. : An Introduction to the Study of Experimental Medicine (trans. by Henry C. Greene). Dover Publications, Inc., New York, 1957, p. 134.