ARTICLES
H
YALINE MEMBRANE DISEASE, oridio-pathic respiratory distress syndrome, is the commonest cause of death in the new-born. Although it has been the subject of
much investigation, its etiology and
patho-genetic mechanisms have remained
ob-scure. Accordingly, there are several
theo-ries about its causation and many opinions
about its optimal therapy, some of these seemingly contradictory. As a result of recent studies, both our own and those of
others, we believe that we have gained
sufficient new insight into the functional
basis of this syndrome to select therapeutic
procedures more rationally than before and
to suggest that the syndrome be renamed
the pulmonary hypoperfusion syndrome.
We believe that the syndrome reflects the calling into action of reflex vasocon-striction which tends to centralize the
circulation of the blood when the fetus or newborn infant is subjected to one or more of several stresses, such as hypoxemia, acidemia, hypothermia, and hypovolemia. This type of response has been observed
in several animal species and tends to
pre-serve blood flow to the brain, heart, and
placenta at the expense of flow to other
organs, especially the gut, the kidneys, and
the lungs and has survival value in the
presence of these stresses. Since the ductus
arteriosus is patent in the fetus and
new-born infant, however, blood flow to the
alveolar capillaries may be virtually
cx-733
EDIT0IuAL NOTE : PEDIATRICS does not usually’ publish preliminary reports,
but for that appearing below we believe an exception is justified. The
corn-l)lete report, referred to as Reference 23, is to be published in Volume 36 of
this journal.
PRELIMINARY
REPORT
THE
PULMONARY
HYPOPERFUSION
SYNDROME
J. Chu, M.D.,1 J. A. Clements, M.D.,2 E. Cotton, M.D.,3 M. H. Klaus, M.D.,4
A. Y. Sweet, M.D.,5 M. A. Thomas, M.D.,#{176}and
W. H.
Tooley, M.D.7(Submitted January 18; accepted for publication February 17, 1965.)
‘Departments of Pediatrics, Western Reserve University School of Medicine, and Mt. Sinai Hospital,
Cleveland, Ohio.
Cardiovascular Research Institute and Department of Pediatrics, University of California Medical
Center, San Francisco; Career Investigator, American Heart Association.
Department of Pediatrics, University of Colorado Medical School, Denver, Colorado.
Departments of Pediatrics, Western Reserve University School of Medicine and Mt. Sinai Hospital,
Cleveland, Ohio. Present Address: Department of Pediatrics, Stanford University School of Medicine
Palo Alto, California.
Departments of Pediatrics, Western Reserve University School of Medicine and Metropolitan
Gen-eral Hospital, Cleveland, Ohio.
Department of Pathology, Faculty of Medicine, University of Singapore, Singapore, Malaysia.
Cardiovascular Research Institute and Department of Pediatrics, University of California Medical
Center, San Francisco, California. Markle Scholar in Academic Medicine.
Work supported in part by USPHS Grants HE-06285, HE-09504-01, HE-01-464-02, and the
Univer-sits’ of California Center for Medical Research and Training with Research Grant GM-i 1329 front the
Office of International Research, NIH.
ADDRESS (for reprints): Editor, Cardiovascular Research Institute, University of California Medical
Center, San Francisco, California 94122.
eluded by pulmonary vasoconstriction, and
ischemic damage is more likely in the lungs
than in other organs. It is for this reason
that we prefer to emphasize the occurrence of pulmonary hypoperfusion in this syn-drome.
The severity of the syndrome varies from
mild and transient postnatal respiratory
difficulty to rapidly progressing distress,
cyanosis and obtundity, and early death.
The chief clinical signs which begin
im-mediately or shortly after birth are labored, grunting respiration with inspiratory
re-tractions and cyanosis. The chest film is
consistent with a diagnosis of pulmonary
atelectasis and infiltration and usually rules
out other causes of respiratory distress.
Bowel sounds are diminished or absent, defecation and diuresis may be delayed,
and edema of hands and feet is often prom-inent. Most commonly, death ensues or
re-covery is well established within about
three days. The outstanding functional
changes are hypoxemia, hypercarbia,
res-piratory and metabolic acidosis, reduced
lung volume and compliance, and large
differences in oxygen and carbon dioxide
tensions between end-expired gas and
sys-temic arterial blood.’ Hyperkalemia often occurs.5 Pressures in the right atrium, right
ventricle, pulmonary artery, left atrium,
and aorta tend to be within or near nor-mal limits for newborn infants.6 There is
evidence, especially late in the syndrome, of large right to left shunts.3’
At autopsy, the lungs are collapsed, firm,
and dark red in color. They expand poorly
and collapse again after expansion.
Micro-scopic sections show alveolar collapse,
over-distension of alveolar ducts, and deposits
of plasma protein in the airspaces. The muscular layer of the walls of the
pulmo-nary arterioles is thick and their lumina are
small, the arterioles appearing like those
of unexpanded fetal lungs, even though the
infant may have lived 48 hours or more.
There are often petechiae in the brain and
meninges and subependymal and
intraven-tricular hemorrhages. Electron microscopic
examination reveals damage in alveolar
epithelial cells, and discontinuities in the
basement membrane. Biochemical studies
of the lung parenchyma show decreases in
neutral lipid, phospholipid, and surface
active lipoprotein fractions. There may also
be abnormalities in the fibrinolytic system of the lung tissue.#{176}’
Though the proximate cause of the
syn-drome is obscure, it is often associated with
premature delivery, antenatal maternal
hemorrhage, maternal diabetes, and with
fetal distress whether of undetermined
origin or related to these complications of pregnancy.
Pulmonary atelectasis with deposition of fibrin in airspaces has long been considered the central fact in this syndrome, a neces-sary and sufficient condition for the mor-phological diagnosis and an adequate ex-planation for the clinical and physiological manifestations. The finding that
“anti-atelectasis factor,” or surface active alveolar
lining substance is not demonstrable in the
lungs of infants that have died with ti is
syndrome reinforced this opinion and
di-rected attention more forcibly to the pri-mary role of atelectasis.h1 Accordingly,
these infants have been treated with
me-chanical inflation of the lungs, administra-tion of aerosolized surface active material
or fibrinolytic enzyme, intravenous
bicar-bonate and glucose solutions, oxygen, and other conservative forms of therapy, but without uniform success. The frequent
fail-ure of these methods to achieve clinical
control suggested that other factors might be of importance in the disease. The nature of at least one such factor, pulmonary vaso-constriction, has become clearer in the
last few years and now appears to us to
be the crucial functional abnormality which must be corrected in order to permit sur-vival.
The reasoning which led us to this
opin-ion had its origin in the demonstration2’13 of pulmonary surfactant and the suggestion
that it is secreted by glandular
ele-ments14’15 of the alveolar epithelium. Such
TABLE I
Con! rol.i
Respira!ny Di8tre..’m
Birth weight (kg),
me-dian and range
Age at death (days),
me-dian and range
Lung weight/body
weight (%)
Lung water (%)
1.5 (30)
[.80 to 3.4J
3 (30)
[0 to 30]
2.46 (30) 81.0 (24) 1.96 (30) 1.91 (28) 0.018( 8) 37.8 (28) 17.4 (26) 3.8 (28) 4.3 (25) 8.3 (23) 1.6 (19)
[.65 to 3.6]
1 (10) [4to 6]
2.16 (16) 82.0 (14) 0.92 (17) 0.84 (16) 0.0015 (11) 26.8 (15) 11.4 (19) 1.8 (15) 9.5 (17) 20.5 (18)
Minimum surface tension
of saline lung extracts
(dynes/cm)5
Numbers are mean values, unless otherwise indicated.
Numbers in parentheses give the numbers of cases on
which the mean or median is taken.
* l)ifference in the means of controls and cases of
respiratory distress is statistically significant (p <.05).
nutrient support. Ordinarily the alveolar
tissue is perfused far in excess of its
re-(lt1ireme1t5, but, with a severely restricted
blood flow, synthesis and secretion of the surfactant might decrease. This view16 was
strengthened by the demonstration that
uni-lateral ligation of a pulmonary artery was
followed by functional, morphological, and
biochemical changes in the lung that bear
striking resemblance to those of hyaline
membrane diseasel7,18
It
was alsosug-gested that lack of surfactant and effusion into airspaces are associated phenomena
because formation of surfactant and
main-tenance of correct alveolar-capillary wall
permeability both require lipoprotein
syn-thesis and may both be deranged in either hyaline membrane disease or following
pul-monary arterial occlusion.16
The etiological link to fetal distress was
provided by experiments1’20 which had
shown that fetal animals react to hypoxia
vitli pulmonary vasoconstriction. Under
such circumstances, almost all of the
out-put of the right ventricle was delivered to the ductus arteriosus, and the alveolar re-gions of the lungs were almost unperfused.
This concept of etiology has received
sup-port from experiments in which the res-piratory distress syndrome was induced in
lambs by causing prolonged hypoxia in the
ewe while the placental circulation was
still intact.2’ It has received further
sup-port from the report of a case22 of
respira-tory distress in an infant that had extensive
atelectasis and fibrin deposition in four of
five lobes, the fifth being well expanded
and lacking fibrin deposition; the four
af-fected lobes were supplied by the
pulmo-nary artery, the fifth by a branch from the
aorta.
We have recently conducted an
inten-sive investigation of respiratory distress in
the newborn and have found additional indications that pulmonary hypoperfusion
is a prominent characteristic of the
syn-drome and that pulmonary
vasoconstric-tion may persist throughout its course.23
We have found that alveolar perfusion can
be increased by infusion of acetyl choline
Lung volume at 40 cm
water (cc per gm)*
Internal area of lungs at
40 Cm water (m2/kg
body Vt.eight)*
Pulmonary vascular
con-ductance (cc/mm/cm blood/gm lung)5
Total lipids of lung
(mg/gm wet)
Choline-containing
plios-pholipids of lung
(mg/gm wet)
highly saturated
choline-containing phospho-lipids of lung-HSCP
(mg/gm wet)5
Minimum surface tension
of HSCP (dynes/cm)5
or sodium bicarbonate. We have also found that raising oxygen tension in the inspired gas is often promptly followed by a de-crease in the arterial carbon dioxide ten-sion in these infants. Among lungs studied
PHYSIOLOGICAL
DEAD
SPACE
(ml)
10-
.
#{149}RDS
o
CONTROL
8-S #{149}
I
.
‘S
#{149} . 0
#{149} SI 0 o
SO
I.
4
0 0So. 0
0 0
o
2-1
1
1
1
1
0
2
4
6
8
10
12
14
TIDAL
VOLUME
(ml)
Fic. 1. Physiological dead space was calculated from carbon dioxide tension in mixed-expired gas and
in blood drawn from the abdominal aorta. Measurements on infants with respiratory (listress were made
before any therapy. RDS = respiratory distress syndrome.
900 - have, that those of infants dying with
res-piratorv distress show atelectasis, hvaline
800 - A.RESPIRATORY DISTRESS
#{149}‘NORMAL membranes, poor expansion, ready collapse,
700 and deficient surface activity. These
al-terations are associated with reduced lipid
600 content and markedly increased pulmonary
vascular resistance of these lungs as
corn-500 pared to those of infants dying from other
#{149} causes. In this note we propose to deal
.400
#{149} #{149}
.
300
#{149} .
200
Fic. 2. Effective pulmonary blood flow (Qe) was
- #{163} calculated from rate of uptake of freon from a
A rebreathing bag, freon solubility in blood, and
j recorded concentration in rebreathing gas mixture.
000 2000 3000 Measurements on infants with respiratory distress
DEAD SPACE TO TIDAL VOLUME RATIO BEFORE AND
AFTER
START
OF CONTINUOUS
INFUSION
OF
ACETYLCHOLI NE
0.5
0.4
0.3 0.9
-0.6
0.2
-I I I I I I J
80 60 40 20 0 20 40 60 80
TIME
IN MINUTES
Fic. 3. Ratio of dead space to tidal volume was calculated from V,/V = 1 - (Pco2 of
mixed expired gas/Pco2 of abdominal aortic blood). Time is given in minutes before and
after acetvl choline infusion was started.
only with the main points in evidence and to offer a few general comments. Detailed
discussion of our methods, results, and
diagnostic criteria and of related work of
other investigators will be presented in
subsequent papers.
Table I summarizes the information
ob-tained at autopsy in 30 control cases and 19 cases of respiratory distress in which
only conventional therapy had been used.
Not all laboratory procedures were
car-ned out in all cases. The two groups arc
comparable in birth weight, lung
weight-body weight ratio, and percentage of water
in the lung tissue. They differ in all other
respects, the most striking being that
aver-age pulmonary vascular conductance in the group with respiratory distress was
one-twelfth that of controls. Additional
studies of these specimens indicated that
the vascular obstruction was in the pul-monary arterial tree. Examination of
his-tologic sections suggested that the site of obstruction was in the arterioles and that constriction of these heavily muscled ves-sels might be responsible. If this severe
constriction and alveolar hypoperfusion
had existed throughout the course of the
syndrome, we could also explain the
mic-roscopic evidence of cellular damage, the
effusion of plasma components into
air-spaces, and the decreased amounts of lipid found in all fractions that were measured, especially the highly surface active
frac-tions.
Physiological studies on 26 infants with
severe respiratory distress produced data
consistent with the notion of alveolar
hy-poperfusion. As shown in Figure 1,
100
-90
80
-E
70-
60-a.
50
-40
-I I I I I I I I I I
dioxide tensions in mixed-expired gas and in blood drawn from the abdominal aorta
was abnormally high in these infants. This elevation of dead space was not due to inadequate tidal volume. Determination of effective pulmonary blood flow revealed
low values in distressed infants, as indi-cated in Figure 2.
We reasoned that if this lack of effective pulmonary blood flow was due to arteriolar constriction, it might be ameliorated by
infusion of acetyl choline” close to the
lungs. The effects of this drug, admin-istered to 12 severely distressed infants through a catheter placed in the umbilical vein and advanced so that its
tip
was in or near the right atrium are documented inFigures 3, 4, 5. No all of our physiological measurements were made in every case. Eleven of the 12 infants so treated re-sponded promptly and favorably. \Vithin a few minutes expiratory complaint ceased,
cyanosis was replaced by a pink flush over
the upper half of the body, and the infants
became more reactive. Bowel sounds were heard, and when the infusion was
con-tinued for several hours diuresis hecam:
evident. (Of these 12 infants, 5 died. Four
of these 5 had received acetvl choline in
small amounts and late in the course
their disease. The fifth survived 7 days and
then died
with
severe intercurrent infection.) The prompt rise in effective ptmlmo-nary blood flow, decrease in dead
space-to-tidal volume ratio, and fall in arterial
car-bon dioxide tension that occurred when
acetyl choline was infused suggest to us
that this drug caused pulmonary vascular
resistance to decrease. The changes in ef-fective blood flow shown in Figure 5
pre-ceded significant rises in lung volume and
compliance. Although pulmonary
vasodila-tation might he expected to cause an
in-crease in venous admixture, arterial oygcii
saturation rose during the infusion of acetvl
choline in 10 of 11 cases in which thc
CARBON
DIOXIDE
TENSION
IN
ARTERIAL
BLOOD
ACETVLCHOLINE
100
80
60
40
20
0
20
40
60
80
00
TIME
IN MINUTES
Fic. 4. Arterial blood was drawn from the abdominal aorta and its Pco2 determined with a Severiughaus
I I I I I I I I I I
700
-600
-500
-400
-300
-200
-100
-100
ACETYLCHOLI
NE
80
60
40
20
0
20
40
60
80
100
TIME IN MINUTES
Fic. 5. See legemid to Fig. 2. lime is given in minutes before and after
acetvl choline infusion was started.
measurement was made. If flow througl i
atelectatic regions of the lungs was
in-creased b’ the drug, a greater increase in
flow must have occurred in ventilated
re-gions, or there must have been a
pr0pr-tionately greater decrease in flow through
other right to left shunts.
Figure 6 d
isplavs
an
addition ilplienoiii-(‘flOU which we consider of great
impor-tance in the pulmonary hvpoperfusion
syn-drome. It has been reported that acidemia
s tromi
gly
intensifies pulmonaryvasoconstric-tion due to hypoxia.2” 25 As shown in this
figure, correction of severe acidemia in au
infant maintained on constant artificial
vemi-tilation with 100% oxygen was accompanied
by a remarkable increase in the arterial
Po.
The
relation between arterial pH andeffective pulmoiiary 1)100(1 flow in 19
in-fants measured prior to specific therapy
is seen in Figure 7.
Figure 8 summarizes
the
points wehay.
uiiade SO far and in a schematic way gives
ur concept of pathogenesis. It emphasizes the complex nature of the functional and
structural relationships and illustrates why the syndrome may be self-perpetuating and progressive. There is objective evi-deuce for each physical or functional
re-lationship in the diagram. Most striking is
that pulmonary vasoconstriction is common to five pathways of physiological feedback. To relieve it should be a primary objective of therapy. Clinical experience as well as cOnsidleratiOn of the relationships set out
in
Figure 8 indicates that both pulmonary and systemic damage accumulate duringthe course of respiratory distress and that effective therapy should l)e delivered as
promptly
as possible. So far we have usedonly acetyl choline, oxygen, and sodium
bicarbonate to dilate the pulmonary
ves-sels, but it may be that another cholinergic,
antiadrenergic, or ganglionoplegic drug
xvii] he more convenient and successful.
CONTROLLED
VENTILATION
P40
f
40pH
7.4
7.3
7.2
7.1
7.0
6.9
6.8
6.7
C
l0
-ACETYLCHOLINE
40
50#{149}RDS
300 - 0 CONTROL 0
0
0
200- 0 0
7.00 7.10 7.20 7.30
ARTERIAL pH
400
-350
-300
-250
-‘4
0
200-150
-I00
50
-20
30
AGE
IN HOURS
Fic. 6. 1,500-gram infant with severe respiratory distress. Arterial oxygen tension an(l ph fell when
acetyl choline was stopped, but rose when sodium bicarbonate xvas infused in amounts calculated to
raise pH to 7.4. f = frequency of respirator, per minute; P = peak airway pressure, cm water.
it is clear that every effort should be made
to avoid maternal hypoxia, acidemia, and systemic hypotension with decreased uter-ine blood foxy. Intervals of diminished
urn-EFFECTIVE PULMONARY
BLOOD FLOW
(mI/mm/kg)
400
100
-#{149}#{149}
#{149} #{149}#{149}
#{149}I
#{149}bilical flow in the fetus should he minimized.
The nexvborn infant at risk should he
watched for intervals of apnea. If these are
long, additional oxygen may be indicated
and respiration may be stimulated or, if nec-essary, assisted. Since chilling may provoke acidemia2o and pulmonary vasoconstriction, we feel that prolonged cooling should be
avoided and that the infant at risk should be placed immediately in a warm environ-ment.
In view of the foregoing evidence xve believe that pulmonary hypoperfusion is the central issue in idiopathic respiratory
I I Fic. 7. See legend to Fig. 2. Measurements were
7.40 7.50 made with the infants breathing OX’s gen (>5)
PULMONARY
VASOCONSTRICTION
ALVEOLAR
-HYPOPERFUSION *
DEFICIENT ANABOLISM
IN ALVEOLAR CELLS
Jr
INCREASED ALVEOLAR
WALL PERMEABILITY
SURFACTANT-DEFICIENT
ALVEOLAR SURFACES
HYPOXEMIA AND
ACIDEMIA
ASPHYXIA AND
ANEROBIC METABOLISM
VENOUS
ADMIXTUREREDUCED
ALVEOLAR VENTILATION
AND ATELECTASIS
+1
FIBRINI4
DEPOSITION_
tJ
_____________________ EFFUSION INTO
_________
AIRSPACES
Fic. 8. Relationships of certain alveolar functions in the hpoperfusion syndrome.
distress of the
newborn.
\Ve
would em-phasize that although we have used acetyl choline as a tool for investigation and have observed that it produces beneficial effects in this syndrome, we do not believe that it will necessarily prove to he the best ther-apeutic item. We are convinced, nonethe-less, that whatever regimen proves mossuccessful will have early pulmonary
vaso-dilatation as an important effect.
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