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(1)

STUDIES

ON

THE

CIRCULATION

IN

THE

NEONATAL

PERIOD

The

Circulation in the

Respiratory

Distress Syndrome

A. M. Rudolph, M.D., J. E. Drorbaugh, M.D., P. A. M. Auld, M.D.,

A. J. Rudolph, M.D., A. S. Nadas, M.D., C. A. Smith, M.D.,

and J. P. Hubbell, M.D.

Department of Pediatrics, Harvard Medical School, the Boston Lying-In Hospital and

the Children’s Medical Center, Boston

Dr. A. M. Rudolph is an Established Investigator of The American Heart Association.

Supported by grants-in-aid (RG-5158) of the Division of General Medical Science, Public Health

Service and (BP-2372) of the Public Health Service, and by The Association for the Aid of Crippled

Children.

PRESENT ADDRESS: (A.M.R.) Department of Pediatrics, Albert Einstein College of Medicine, New

York 61, New York.

551

PEDIATRICS, April 1961

P

ROFOUND cilangeS in the cardiovascular

system occur in the newborn animal in

adaptation from a placental to a pulmonary

circulation. It is not unreasonable to expect

that occasionally the normal progression of

circulatory changes may be disturbed. The

possible role of such a disturbance of the

circulation in the production of the

respira-tory distress syndrome (hyaline membrane

disease) has been postulated.’

Although intensive studies of the changes

in the circulation after birth have been

made in animals by Barclay et al.2 and

Dawes et a!.’ only limited information on

the changes in human infants is available.4

The purpose of the present study is to

further delineate the changes in the

circula-tion of infants with normal cardiovascular

and pulmonary function and to determine

whether a circulatory disturbance may be

responsible for production of the syndrome

of respiratory distress in certain newborn

infants.

MATERIAL AND METHODS

Studies of the circulation were conducted by

means of cardiac catheterization in 28 newborn

infants. These infants were carefully observed

for evidence of respiratory distress, and were

separated into three groups on the basis of the

severity and duration of respiratory signs.5

Group I comprised 19 infants either with no

signs of respiratory distress or with mild

eva-nesccnt symptoms. Four of these babies showed

unquestionable evidence of mongolism, and

one was microcephalic. Eight of the 19 were

infants of diabetic mothers. Their ages at the

time of cardiac catheterization ranged from 2

to 34 hours and their weights from 2.414 to

4.090 kg. Fourteen of these infants were males

and five females. (It is important to appreciate

that infants of diabetic mothers are heavier at

the same gestational ages than those born of

nondiabetic mothers.) Gestational ages of these

babies ranged from 36 to 41 weeks. The

method of delivery was by pelvic route in 14,

and by cesarean section in five cases. The

clinical condition of all infants at the time of

delivery and at the time of study was not

re-markable.

All pressures were measured with the zero

reference level at the midchest level in the

an-teroposterior diameter.

Group II consisted of nine infants with mild

respiratory distress. All these were infants of

diabetic mothers. Four infants were males and

five, females. The ages at time of study varied

from 2 to 11 hours, and weights were between

2.073 and 3.181 kg. Their gestational ages at

birth were 33 to 39 weeks; two of the nine

infants were born by pelvic delivery and seven

by cesarean section. Seven of these babies were

considered to have mild respiratory symptoms,

and two were thought to show moderate

dis-tress. Group III included 10 infants with severe

respiratory distress. Seven of these infants were

males and three, females. Five of this group

were infants of diabetic mothers. Their ages

at the time of catheterization were 3 to 21

hours and weights were 1.278 to 2.869 kg. The

gestational age of these infants ranged from

(2)

de-livery and four by cesarean section. These

in-fants all had severe symptoms, and 8 of the 10

died with increasing respiratory symptoms 3

to 58 hours following the catheterization study.

Necropsy confirmed the presence of severe

hyaline membrane disease in these infants.

There was also no evidence to indicate that

the catheterization procedure had contributed

to the fatal outcome of these infants.

The decisions to perform studies on the

in-fants were made only after careful clinical

ob-servation. Radiologic and electrocardiographic

studies were carried out for all the infants with

respiratory symptoms and for the majority of

those with no respiratory distress. The

pro-cedure was performed after full discussion with

and consent of at least one of the parents. No

medicaments or anesthetics were administered.

Oxygen therapy by inhalation was continued

during catheterization in the 10 infants with

severe symptoms, all of whom were receiving

oxygen before the procedure. The infants

without symptoms, or with mild symptoms, did

not receive oxygen.

In 15 newborn infants cardiac

catheteriza-tion was attempted by inserting the catheter

into the umbilical vein, wih the aim of

manip-ulating it through the ductus venosus into the

inferior vena cava and then into the heart. In

view of the tendency for the catheter to enter

portal veins, with difficulty in maneuvering

be-yond the ductus venosus, the attempt was

abandoned in five instances. In 10 infants,

in-eluded in this report, the catheter could be

manipulated into the heart, but in only 2 of

these was it possible to pass the catheter into

the pulmonary artery. In the remaining 28

in-fants, the catheter was inserted through the

right saphenous vein in the groin. Under local

procaine anesthesia, a small incision was made

just below the groin and the saphenous vein

was readily isolated. A 50-cm-long No. 4F

Leh-man catheter was inserted in most instances,

but in two infants a 35-cm-long No. 3.5F

Lehman catheter was used in view of the small

size of the vein.

After the catheter was passed into the right

atrium from the inferior vena cava, an

immedi-ate attempt was made to enter the superior

vena cava. The catheter was then again

with-drawn and manipulated into the right ventricle.

A very careful continuous monitoring of the

electrocardiogram was then conducted with the

aid of an oscilloscope, and attempts were made

to pass the catheter into the pulmonary artery.

The catheter was rapidly withdrawn if

yen-tricular ectopic beats were induced;

conse-quently in only 22 instances was the pulmonary

artery catheterized. In the other 16 instances

the attempts to enter the pulmonary artery

were abandoned in view of the induction of

numerous ectopic beats during these

manipu-lations.

The catheter was also passed through the

ductus ateriosus in 20 of the 22 infants whose

pulmonary artery was entered. As the tip of

the catheter was manipulated beyond the

pul-monary valve, it usually preferentially followed

a course through the ductus arteniosus into the

descending aorta. In view of the relatively

small size of the vessels, it was difficult to assess

whether the tip of the catheter was located in

the main pulmonary artery, in the ductus

arteniosus itself, or in the aorta. Persistent

at-tempts were therefore made to direct the

catheter into the left or right main pulmonary

artery. In the occasional instance in which this

was not accomplished, the pulmonary arterial

pressure and blood sample was obtained in

the main pulmonary artery just beyond the

pulmonary valve.

The left atrium was entered in 27 infants

by passage of the catheter through the

fora-men ovale. A pressure gradient between left

and right atrium was measured as the catheter

was withdrawn from the left to the right atrium.

Cineangiography to establish the presence of a

ductal left-to-right shunt was performed in

seven infants, by injection of 2 to 2.5 ml of

75% sodium diatrizoate (Hypaque sodium) into

the left atrium.

The fluoroscopic examinations during

manip-ulation of the catheter and the cineangiography

were performed with the aid of a 5-in. Philips

roentgen image intensffier. Pressures were

con-tinually monitored with the use of a Statham

P 23 D pressure transducer.

Electrocardio-grams and pressures were recorded on a

San-born direct-writing oscillograph. Oxygen

satu-ration was measured by a spectrophotometric

method.6

RESULTS

The hemodynamic observations in group

I, the 19 infants without significant

respira-tory symptoms, are presented in Table I.

One patient was studied both at 5 and 26

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554

from - 3.0 to + 4.5 mm Hg; left atrial

pres-sures ranged from -2.0 to +7.0 mm Hg.

The left atnial pressures were higher than

by 1.0 to 4.5 mm Hg except in two cases; in

one the pressures were equal, and in the

other right atrial pressure was 0.5 mm Hg

higher. Right ventricular systolic pressures

were measured in 16 of these infants and

ranged from 33 to 80 mm Hg. Pulmonary

arterial systolic pressures ranged from 30 to

68 mm Hg, with an average of 50.5.

Pulmo-nary arterial diastolic pressures ranged

from 8 to 42 mm Hg, with an average of

24.5; the mean pressure ranged from 15 to

49 mm Hg, with an average of 35. The

sys-temic arterial pressures were 48 to 75

sys-tolic, with an average of 61 mm Hg; 28 to

40 diastolic, with an average of 35.5 mm

Hg; and 38 to 51 mean pressure, with an

av-erage of 45 mm Hg.

As shown in Table I, several infants had

a small increase in saturation of blood at

the atrial level as compared to superior vena

caval blood. This could represent some

shunt through a foramen ovale, but it

could be due to addition of more fully

satu-rated blood from the inferior vena cava, as

suggested in one instance. Since the major

interest in these studies was in connection

with the ductus arteriosus, calculations of

pulmonary to systemic flow ratio were made

using right ventricular samples for mixed

venous saturations, and thus the pulmonary

to systemic flows presented in Tables I, II

and III actually reflect the size of the ductal

shunt.

In the eight infants for whom it was

pos-sible to obtain reliable saturation data from

the pulmonary artery, there was no

evi-dence of any significant difference in

oxy-gen saturation between right ventricle and

pulmonary artery, indicating the absence of

any significant left-to-right shunt through

the ductus arteriosus in four. A very small

left-to-right shunt through the ductus was

evident in the other four, with a calculated

pulmonary to systemic flow ratio varying

from 1.2:1 to 1.6:1.

Oxygen saturation in the systemic artery

ranged from 75 to 96%. In three instances,

the arterial saturation was somewhat less

than the left atrial saturation, suggesting

the presence of a small right-to-left shunt,

probably at the ductal level. In one

in-stance, the left atrial saturation was less

than pulmonary venous saturation,

suggest-ing a right-to-left atrial shunt. Left atrial

blood samples showed saturations above 90%

in all except two infants, in whom the

satura-tions were 80 and 82% respectively. In one of

these a pulmonary venous sample showed a

saturation of 91%, indicating some

right-to-left shunt. The possibility of a disturbance

of a ventilation perfusion ratio as a cause of

unsaturation in some of these infants should

also be considered.

Table II presents the hemodynamic data

in the nine infants in Group II with mild

respiratory symptoms.

Right atrial pressures in this group

ranged from - 2.0 to + 8 mm Hg and left

atrial pressures from - 0.5 to 9 mm Hg.

There was a left-to-right atrial pressure

gradient in all, ranging from 0.5 to 6.5 mm

Hg. Right ventricular systolic pressure

ranged from 45 to 85 mm Hg. Pulmonary

arterial pressure was measured in eight of

the nine infants. The systolic pressures

var-ied between 40 and 60 mm Hg, with an

av-erage of 51 mm Hg; diastolic pressures

var-ied from 20 to 35, with an average of 37.2

mm Hg. Systemic arterial pressures ranged

from 48 to 100, with an average of 65.2 mm

Hg in systole, and from 22 to 63, with an

average of 41 mm Hg in diastole; mean

systemic pressures ranged from 35 to 76,

with an average of 51.5 mm Hg.

Oxygen saturation data indicated the

presence of a small left-to-right shunt at the

atrial level in two infants, in whom the right

atrial saturation was 5 to 8%, and 12% higher

than caval saturation, respectively. It is of

interest that these two infants had the

largest pressure gradients between left and

right atria, measuring 5 and 6.5 mm Hg

re-spectively. Adequate sampling from the

pulmonary artery was possible in eight of

the nine infants. In four there was no

dif-ference in saturation between right

ventri-cle and pulmonary artery, and in the other

four there was only a small increase in

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level, indicating the presence of a small

left-to-right shunt through the ductus arteriosus.

The ratios of pulmonary to systemic flows

were 1.2:1 to 1.6:1 in these four babies.

Systemic arterial oxygen saturation

ranged between 83 and 94%. In one infant,

a saturation of 86% was raised to 95% by

oxy-gen administration. In two infants the

an-terial saturation in descending aorta was

slightly lower than that in left atrium,

mdi-eating the presence of a small right-to-left

shunt through the ductus arteniosus. Left

atrial saturation, where measured, was 90%

or above, in all but two instances. In these

two babies it was 85 and 86% respectively.

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10 infants in Group III are presented in

Table III.

Right atrial pressures ranged from - 6.5

to 0 mm Hg and left atrial pressures from

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5.5

to 6-9 mm Hg. The pressure gradients

from left to right atrium ranged from 1 to

6-9 mm Hg. Right ventricular systolic

pres-sures ranged from 25 to 35 mm Hg.

Pulmo-nary arterial pressure was measured in

7 of the 10 infants. Pulmonary arterial

systolic pressures ranged from 23 to 52 mm

Hg, with an average of 38.5; diastolic

pres-sures varied between 9 and 30 mm Hg, with

an average of 19 mm Hg; mean pulmonary

artery pressures were 16 to 40, with an

aver-age of 26.5 mm Hg. Systemic arterial

pres-sure was recorded in six infants; systolic

pressure varied from 29 to 60, with an

aver-age of 46 mm Hg; diastolic pressure from

16 to 35, with an average of 28.5 mm. Hg;

and mean pressure from 20 to 45, with an

average of 36 mm Hg.

In all these cases oxygen saturation data

were obtained while the infants were

breathing 100% oxygen, administered by a

loosely-fitting mask. A significant increase

in oxygen saturation of 34 and 11%

respec-tively was noted between superior vena cava

and right atrium in two infants, indicating

the presence of a left-to-right shunt through

the atrial septum. A further increase in

satu-ration was noted in one of these infants at

the ventricular level, possibly due to a

streaming effect. No congenital cardiac

anomalies were demonstrated in those

stud-ied at necropsy. Oxygen saturation was

measured in the pulmonary artery in seven

infants. An increase in oxygen saturation of

4 to 19% was noted at the pulmonary artery

level. The actual size of the left-to-right

shunt through the ductiis was difficult to

estimate accurately, since there was also a

right-to-left shunt in some instances.

How-ever, a very large left-to-right shunt through

the ductus arteriosus was present in all

seven infants in whom this could be

esti-mated. Systemic arterial oxygen saturation

in the descending aorta (during oxygen

administration) ranged from 63 to 98%. The

infant with the lowest saturation of 63% had

a low left atrial saturation (80%) and a very

large right-to-left shunt through the ductus

arteriosus. The left atrial saturation in the

other five infants in which it was measured,

was above 90%.

A comparison of the hemodynamic data

from these three groups of patients indicates

that there is essentially no difference

be-tween infants with no respiratory distress

and those with mild respiratory distress.

Their average pulmonary arterial pressures,

systemic arterial pressures and left and right

atrial pressures are quite similar. About

one-half of each group had no ductal

left-to-right shunt, and the others had only small

left-to-right shunts through the ductus with

pulmonary to systemic flow ratios 1.6: 1 or

less in all instances. The infants with severe

respiratory distress differed considerably

from the other two groups. The average

pul-monary arterial pressures were lower, and

the average mean pulmonary arterial

pres-sure was about 10 mm Hg lower than in the

other groups. The systemic arterial systolic

and diastolic pressures were also lower, and

the average mean systemic arterial pressure

was about 10 mm Hg lower than in the

nor-mal and mildly distressed group. The group

with severe symptoms also all showed

evi-dence of a widely patent ductus arteniosus,

with large left-to-right shunt, and in

sev-era! instances, an accompanying right-to-left

shunt.

In view of the great diversity of these

in-fants with regard to period after birth when

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TABLE IV

ANALYSIS OF AGE, WEIGHT, GF.STATIONAL AGE AND MODE OF DELIVERY IN INFANTS WITH AND WITHOUT

RESPIRATORY DISTRESS*

Cases

(no.)

Average Gest. Age

Average Wt. (Ib)

Average Age (hr)

Caesarian Section

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Mild distress

Severe distress

8 8

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7.5 6.5

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18.0 5.4

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3

S These observations were compiled from early studies in which the pulmonary artery was entered by tile

catherer.

t Infant of diabetic mother.

of delivery, an attempt was made to

deter-mine the possible role of these factors in

explaining the striking hemodynamic

dif-ference in the infants with severe

respira-tory distress. At first analysis (Table IV) it

did not appear that any of these factors

were significant, as there was considerable

overlap in each group. However, a more

complete analysis produced some

interest-ing observations.

A graph, not shown, relating pulmonary

arterial systolic or mean pressure to age in

hours at the time of study indicated that

there is a tendency for the pressure to

de-crease gradually after birth. The severely

distressed infants had pressures

consider-ably lower than the other two groups. In

order to plot a larger number of patients,

right ventricular systolic pressure was

re-lated to age, as shown in Figure 1. This

demonstrates a suggestive decrease of

pres-sure with age with a linear regression

of y = - 0.227x + 58 for the normal and

mildly distressed groups, whereas the

se-verely distressed infants had lower pressures

at the same age, with a linear regression of

y = -0.45x + 45.

When right ventricular systolic pressure

is plotted against the weight of the infants

(

Fig. 2) it is demonstrated that the larger

the infant, the higher is the right ventricular

systolic pressure. Also, although there is

some overlap, it is apparent that the

se-verely distressed infants were smaller infants

and it is possible that the lower right

yen-tricular and pulmonary arterial pressures

were related to this factor rather than to the

fact that they had the respiratory distress

syndrome. The linear regression for all

groups is represented by y 8.2x + 26.

The relationship of right ventricular

sys-tolic pressure to gestational age is similar to

that of right ventricular pressure to weight.

The greater the gestational age of the

in-fants, the higher the right ventricular

sys-tolic and pulmonary arterial pressures

(

Fig.

3). Again, the more premature infants were

those with severe respiratory distress, so

that it is not possible to separate the role of

maturity and that of the distress syndrome in

relationship to the lower right ventricular

systolic pressures.

An evaluation of the relationship

be-tween age of the infants, gestational age

and weight, and the presence of a

widely-patent ductus arteriosus is very difficult.

Figures 4, 5 and 6 demonstrate the

rela-tionship between the rise in oxygen

satura-tion at the pulmonary arterial level, and the

infants’ weight, age and gestational age.

The difference in oxygen saturation does

not truly represent the size of the

left-to-right shunt, as this depends also on the

ac-tual level of saturation in mixed venous

blood.7 The presence of large left-to-right

shunts in the distressed infants is again

shown, and although there is no definite

re-lationship to age, weight or gestational age,

it appears that large shunts are commoner

in the immature infants.

The cineangiographic studies confirmed

the presence of a small ductal shunt in

three infants with a small calculated shunt,

(9)

0

70

60

50

40

30

0

o.

0

0

.

0

0 0

0

0

0

0

0 0

0

0

0

0

0 0

0 0 0

00 0

0

.

S

5 0 5

AGE HOURS

0

0

0

I0

C 20 25 30

H

z

80

20

0 .JJ4Q

a

0N0i& +MLD

. SEVERE

FIG. 1. Relationship of right ventricular systolic pressure to age of infant.

no ductal shunt was found by saturation

data, and demonstrated a very large shunt

in one of the severely distressed infants.

DISCUSSION

Hemodynamic Changes in the Normal

Infant after Birth

Circulatory adjustments to extrauterine

life are not completed within the first few

minutes after birth but are extended over

several hours and possibly several 8

The available information regarding the

hemodynamic status of the infant with

nor-mal circulatory and pulmonary systems in

the first 24 hours of life is very meager.4

The elegant studies of Dawes3 in fetal

lambs have demonstrated that ventilation

of the lungs decreases pulmonary vascular

resistance and thus results in a great

in-crease in pulmonary blood flow. Associated

with this decrease of pulmonary vascular

resistance, there is a reversal of the flow

through the patent ductus arteriosus from

the fetal right-to-left direction, to provide

a left-to-right shunt. This left-to-right shunt

through the ductus arteriosus has been

shown to persist in the fetal lamb for at

least several hours after ventilation of the

lungs and possibly aids in increasing

sys-temic arterial saturation when the lungs are

(10)

80

70

60

50

40

30

20

0 I.?

0

0

S

0

0 0 0

0

0

0 0

0

S 0

0 S 0.1

0 0 0

0

S

8 0

S

0 NORMA1

0 FvILD

S SEVERE

. NORMAL, MILD

AND SEVERE

S

0

4

0 2

WEHT KILOGRAMS

3

0

.

Fic. 2. Relationship of right ventricular systolic pressure to weight of infant.

The presence of a ductal left-to-rght

shunt in normal newborn infants was first

inferred from dye dilution studies by Prec

and Cassels1#{176}and also by cardiac

catheteri-zation studies by Adams and Lind4 and

Rowe and James.8 The physiologic studies

of Adams and Lind suggested that there is

a very large ductal left-to-right shunt in

the normal newborn infant. Analysis of their

data suggests, however, that in three of the

eight babies studied, the catheter was in the

ductus or aorta when the “pulmonary

ar-tenial” sample was obtained, in two the data

were inadequate, in one there was no ductal

shunt, in one the shunt was minimal and in

the remaining infant there was a rise in

oxy-gen content of 2.8 vol % in right ventricular

blood as compared to right atrial blood, and

a further rise of 3.3 vol % in pulmonary

arterial blood. Although this appears to

rep-resent a large ductal shunt, the data are

dif-ficult to evaluate.

The data in the present study indicate

that the ductus is functionally closed,

al-though anatomically patent, in many

nor-ma! infants in the first day of life. In some

infants, a small left-to-right shunt occurs

through the ductus, with a pulmonary to

systemic flow ratio of 1.6 : 1 or less. As

shown in Figure 4, none of the infants over

15 to 20 hours of age with normal

(11)

80

8

70

0 0

60 0 0 0 00

0

0

S 0

50 0 0

a . 0 0

S 0

40 0 5 0

S

0 0

30 S 0

S S

20 0 N0fV1AL

aMLD

SSEVERE

0

30 31 32 33 34 35 36 37 38 39 40 41

AGE WEOKS

FIG. 3. Relationship of right ventricular systolic pressure to gestational age of infant.

20#{149}

.

0 NORMAL

0 MLD

. SEVERE

15

Li

a

j:

10

o#{149}o

5

ci 0

0

0 0

0 0 0

0 i 0 0 , V ;

0 5 15 20 25

AGE HOURS

Fic. 4. Relationship of difference in oxygen saturation between pulmonary artery (PA) and mixed venous

(12)

20 0 NORMAL

0 MILD

S . SEVERE

.

5

S

#{149}5

I0

S

0

S 0 0

5

0 0

0 0 0

0 0 0

,‘ 0 0 0 0

WEIGHT KILOGRAMS

4

S

S

S

20

5

0

5

0

Li->

cr

0 GROUPS I AND K

S GROUP

0

0

a 0

0

0

.

0

0

S

S

0

0

0 0

0

U-. U-0

0c0

- I

0

a:

Fic. 5. Relationship of difference in oxygen saturation between pulmonary artery (PA) and mixed venous

blood (MV) to weight of infant.

saturation in the pulmonary artery of

greater than 2%. The difference in these

findings as compared to those of Adams

and Lind4 and Rowe and James8 may be

re-lated to the fact that no premedication was

employed in our studies. It is also interesting

that in the studies of Rowe and James the

youngest infant, aged 2 days, had no

demon-strable ductal shunt, whereas five infants

between 5 and 11 days had evidences of a

shunt. These findings, and those of

El-dnidge

et al.1’

indicate that the ductus may

be anatomically open, although

function-ally closed for the first 7 to 10 days of life,

30 32 33 34

GESTA110Ni GE WEEKS

36 37 38

FIG. 6. Relationship of difference in oxygen saturation between pulmonary artery (PA) and mixed venous

(13)

ARTICLES

providing physiologic confirmation of the

anatomical studies of Mitchell.12 The

pres-ent observations also corroborate the

aus-cultatory evidences of patent ductus

arteri-osus demonstrated by Burnard,13 and by

Braudo and Rowe.14 The murmur of patent

ductus arteriosus was noted to be much

commoner by these authors in the first 10

hours of life and was quite unusual beyond

this age.

The pulmonary arterial pressure varied

greatly in the first day of life. In some

in-fants it had dropped very rapidly, almost to

adult levels, within a few hours, whereas in

others, the pulmonary arterial pressure was

still close to systemic levels at the end of

the first day. There was, however, a

sugges-tion of a gradual decrease in right

ventricu-lar and pulmonary pressure during the first

day. The height of the pulmonary arterial

pressure was in no way related to the

pres-ence or absence of a ductal shunt in the

normal or mildly distressed infants. It

ap-peared that the factors determining the

presence of a left-to-right shunt were not

only a decrease in pulmonary vascular

re-sistance, but the degree of ductal

constric-tion.

Hemodynamic Observations in Infants

with Severe Respiratory Distress

The infants with severe respiratory

dis-tress showed definite differences in their

cir-culatory status as compared to the normal

and mildly distressed infants. Their

sys-temic arterial and pulmonary arterial

pres-sures were considerably lower; they all had

a widely patent ductus arteriosus with a

large left-to-right shunt and in many

instan-ces a right-to-left shunt through the ductus.

A preliminary report of some of these data

has been presented,#{176} and first analysis

sug-gested that all the circulatory phenomena

were associated with the respiratory distress

syndrome. A more complete analysis has

indicated, however, that although the lower

systemic and pulmonary arterial blood

pres-0 Society for Pediatric Research, Buck Hill Falls,

May, 1959.

sure may be related to the severe respiratory

distress, it is also possible that prematurity

or immaturity may explain these differences.

The infants with severe respiratory distress

were smaller and of lower gestational age

than the normal and mildly distressed

in-fants. In order to establish the possible

rela-tionship of low pulmonary and systemic

arterial blood pressures to the respiratory

distress syndrome, it will be necessary to

procure a great deal more information in

infants of comparable age, weight and

ges-tational age.

The association of a widely patent ductus

arteriosus with severe respiratory distress

appears to be possibly related to the

dis-ease, but it could be related to immaturity.

In view of the small numbers of infants

studied, of the variation in circulatory

ad-justment after birth, and of possible

differ-ences in the response of the ductus in the

premature infant, the significance of this

observation cannot be accurately evaluated

at present. These findings, however,

sup-port those of Burnard,15 who noted that

mur-murs are more commonly observed in

in-fants with respiratory distress and suggested

that the ductus may be patent in these

infants.

The relationship of a widely patent

due-tus arteriosus to respiratory distress

syn-drome could be explained in several ways.

First, patent ductus arteriosus may be

responsible for the disease. A widely patent

ductus arteriosus may produce an excessive

load on the left ventricle, with the features

of left ventricular failure in early infancy.

The possible relationship of cardiac failure

to the development of the respiratory distress

syndrome has been suggested by Lendrum’

and Shanklin,16 who found in a series of

necropsies in the neonatal period that, “in

the presence of what seems to be a

physio-logically deficient left ventricle, 90% of these

cases showed hyaline membrane.”

The hyaline membrane found in the

lungs of infants dying of the respiratory

distress syndrome has been demonstrated

by Gitlin and Craig17 and Lynch and

(14)

in-fants’ blood proteins. Although Landing19

has not found a close association between

the presence of hyaline membranes and

pul-monary edema, Lynch2#{176}in his experimental

studies observed that pulmonary edema

in-variably preceded hyaline membrane

for-mation. Bound

et

al.21 have stressed the

pres-ence of intense congestion and edema in

affected infants, and in some instances

pul-monary edema has been the most striking

pathologic finding.

The presence of pulmonary edema and

the possible relationship to cardiac failure

has suggested the possible implication of

the widely patent ductus with left

yen-tnicular failure as the cause of the

respira-tory distress syndrome. Burnard2 has

pre-sented evidence that the heart is enlarged

and, if the infant recovers, undergoes a

rapid reduction of size, adding further

sup-port to the possibility of presence of

car-diac failure. He has also indicated that

heart murmurs are commoner in infants

with respiratory distress than in normal

infants’5

The objection may be raised that

pul-monary edema in adults usually does not

develop until pulmonary venous and left

atrial pressure are elevated to a level of 25

mm Hg. The left atrial pressures in the

infants with severe respiratory distress were

not significantly elevated, and this raises

some doubts regarding the role of left

yen-tricular failure. The capillaries of infants

may, however, be more permeable than

adult vessels, and evidence of left

ventricu-lar failure has been observed in infants

with congenital heart disease, with left

at-rial pressures of 10 to 15 mm Hg. It is also

important to appreciate that transmural

pressure is most significant; in infants with

respiratory distress, the intrapleural

pres-sure may reach high negative levels, and

thus the effective left atrial, pulmonary

venous, and transmural pressuies may be

considerably elevated.

Thus a considerable amount of evidence

has been accumulated to implicate a widely

patent ductus as the cause of the

respira-tory distress syndrome. The relationship has

not, as yet, been conclusively demonstrated.

Second, the observation that several

in-fants studied had low systemic and arterial

blood pressures indicated the possibility

that infants with severe respiratory

dis-tress may have generalized vasodilation or,

rather, lack of vasoconstrictor response.

Measurements of systemic arterial pressure

by indirect od24 indicate that the

blood pressure in these infants is low soon

after birth and that it remains low unless

recovery ensues. Although there is a marked

decrease of pulmonary vascular resistance

accompanying the ventilatory process, the

pulmonary vessels maintain a state of

vaso-constrictor tone at least for several hours

after birth normally, as shown by the

per-sistence of a high pulmonary arterial

pres-sure. Inability of the pulmonary vessels to

maintain this vasoconstriction may allow for

a very large left-to-right shunt in the

pres-ence of a patent ductus. Furthermore, it is

possible that the ductus arteriosus itself may

also not undergo its normal constriction,

be-cause of the same generalized lack of

vaso-constrictor tone. The prolonged pulsations

of the umbilical arteries observed in infants

with distress may similarly be related to lack

of umbilical vessel constriction.25 The cause

of the poor vasoconstrictor response

pre-sented in this hypothesis is not known,

but it could be related to immaturity of the

vasomotor response systems.

Third, the possibility that the large

left-to-right shunt through the ductus may be

oc-casioned by severe respiratory distress

certainly has to be entertained. It seems

unlikely that the response of the ductus

arteriosus itself can be affected by a high

negative intrathoracic pressure, since the

vessel has a thick muscular wall. However,

the large negative pressures developed

could possibly increase the size of the shunt

through a ductus which is partially patent,

by opening up small pulmonary blood

yes-sels. But, as has been shown by Dawes

et

al.,

alveolar expansion is necessary to

decrease pulmonary vascular resistance;

and since the lungs in the respiratory

(15)

ex-ARTICLES

panded, it is not very likely that this

mecha-nism is responsible for the large ductal

shunt.

CONCLUSIONS

The studies on the circulatory status of

normal infants in the neonatal period have

demonstrated that the pulmonary arterial

blood pressure remains elevated for at least

several hours after birth and gradually

drops to near adult levels within hours or

a few days. The pressure level appears to

be related to gestational age and birth

weight, being higher in mature infants.

The ductus arteriosus gradually closes

after birth in normal newborn infants, but

a small left-to-right shunt may be

detect-able during the first 10 to 15 hours.

Al-though functionally closed after this period,

the ductus is anatomically patent and may

reopen under appropriate stimuli during

the first 7 to 10 days of infancy.

Studies of infants with severe respiratory

distress syndrome (hyaline membrane

dis-ease) revealed pulmonary arterial pressures

lower than in infants with “normal”

circu-lation, but since these infants were smaller

and less mature, the significance of this

finding could not be evaluated.

All infants with severe respiratory

dis-tress syndrome also had evidences of a

widely patent ductus arteriosus with a large

left-to-right shunt. In the small number of

babies studied, this finding did not appear

to be associated with birth weight or

ges-tational age. However, no definite

differen-tiation between the association of the

wide-ly patent ductus with prematurity or with

the respiratory distress syndrome could be

made on the basis of the present study.

The possible role of the widely patent

ductus arteriosus as a cause of left

ventricu-lar failure, pulmonary edema, the

respira-tory distress and hyaline membrane

forma-tion is considered. The alternate hypothesis

that there is a generalized lack of

vasocon-striction possibly related to prematurity,

affecting systemic and pulmonary blood

vessels as well as the ductus arteriosus, is

also presented. Obviously no far reaching

therapeutic conclusions in regard to hyaline

membrane disease can be reached on the

basis of the limited information presented.

Nevertheless, it seems fair to say that

serious consideration should be given to

attacking the respiratory distress syndrome

from the circulatory view point. The use of

digitalis has been repeatedly suggested, and

good results have been claimed.26

SUMMARY

Hemodynamic measurements by means

of cardiac catheterization were obtained in

38 infants in the first 30 hours after birth.

Nineteen of these infants were considered

to have normal circulatory and respiratory

systems. Nine had mild respiratory distress,

and 10 had severe respiratory distress.

The circulatory systems of infants with

mild respiratory distress did not

appreci-ably differ from the normal. Some infants

in both these groups showed evidences of

patency of the ductus arteriosus with a

small left-to-right shunt for the first 10 to

15 hours after birth.

The infants with severe respiratory

dis-stress had widely patent ducti, with large

left-to-right shunts and, in some instances,

right-to-left shunts. The pulmonary arterial

and systemic arterial pressures were lower

in these infants as compared to the normal

and those with mild respiratory symptoms.

These characteristics of the severely

dis-tressed infants could be related to the

dis-ease process, but may be due to prematurity

alone.

The possible role of left ventricular

fail-ure associated with a large left-to-right

ductal shunt is discussed. A generalized

lack of vasoconstrictor tone could possibly

be responsible for systemic and pulmonary

arterial hypotension as well as for the widely

patent ductus arteriosus.

REFERENCES

1. Lendrum, F. C. : The pulmonary hyaline

membrane as a manifestation of heart

failure in the newborn infant.

J.

Pediat.,

47:149, 1955.

(16)

Pntch-ard, M. M. L. : The Foetal Circulation.

Oxford, Blackwell, 1944.

3. Dawes, G. S., et al.: Changes in the lungs

of the newborn Iamb.

J.

Physiol., 121:

141, 1953.

4. Adams, F. H., and Lind,

J.

: Physiologic

studies on the cardiovascular status of

normal newborn infants (with special

reference to the ductus arteriosus).

PEDI-ATRICS, 19:431, 1957.

5. Drorbaugh,

J.

E., et al.: Clinical

observa-tions on the cardiopulmonary status of

infants with hyaline membrane disease.

J.

Dis. Child. 98:145, 1959.

6. Gordy, E., and Drabkin, D. L. :

Spectro-photometric studies. XIV. Determination

of oxygen saturation of blood by a

sim-plified technique applicable to standard

equipment.

J.

Biol. Chem., 227:285,

1957.

7. Rudolph, A. M., and Cayler, G. G. :

Car-diac catheterization in infants and

chil-dren. Pediat. Clin. N. Amer., 5:907,

1958.

8. Rowe, R. D., and James, C. S. : The normal

pulmonary arterial pressure during the

first year of life.

J.

Pediat., 51 : 1, 1957.

9. Born, G. V. R., et a!.: The relief of central

cyanosis caused by pulmonary

arterio-venous shunts by construction of an

arti-ficial ductus arteriosus.

J.

Physiol., 130:

167, 1955.

10. Prec, K.

J.,

and Cassels, D. E. : Dye

dilu-tion curves and cardiac output in

new-born infants. Circulation, 11:789, 1955.

11. Eldridge, F. L., Hultgren, H. N., and

Wig-more, M. E. : The physiologic closure of

the ductus arteriosus in newborn

in-fants : a preliminary report. Science,

119:731, 1954.

12. Mitchell, S. C. : The ductus arteriosus in

the neonatal period.

J.

Pediat., 51:12,

1957.

13. Burnard, E. D. : A murmur from the ductus

arteriosus in the newborn baby. Brit.

Med.

J.,

1:860, 1958.

14. Braudo, M., and Rowe, R. D. : Quoted by

Rowe, R. D., in Adaptation to

extra-uterine life, 31st Ross Conference on

Pediatric Research, p. 38.

15. Burnard, E. D. : The cardiac murmur in

relation to symptoms in the newborn.

Brit. Med.

J.,

1:134, 1939.

16. Shanklin, D. R. : Cardiovascular factors in

development of pulmonary hyaline

membrane. Arch. Path., 68:49, 1959.

17. Gitlin, D., and Craig,

J.

M. : Nature of

hyaline membrane in asphyxia of

new-born. PEDIATJIICS, 17:64, 1956.

18. Lynch, M.

J.

G., and Mellor, L. D. :

Hy’-aline membrane disease of premature

lungs.

J.

Pediat., 47:275, 1955.

19. Landing, B. H. : Pathologic features of

respiratory distress syndrome in

new-born infants. Amer.

J.

Roentgenol., 74:

796, 1955.

20. Lynch, M.

J.

G. : Hyaline membrane

dis-ease: Further observations.

J.

Pediat., 48:

165, 1956.

21. Bound,

J.

P., Butler, N. R., and Spector,

W. G. : Classification and causes of

pen-natal mortality. Brit. Med.

J.,

2:1191,

1956.

22. Burnard, E. D. : Changes in heart size in

the dyspneic newborn baby. Brit. Med.

J.,

1:1495, 1959.

23. Neligan, G. A. : The systolic blood pressure

in neonatal asphyxia and the respiratory

distress syndrome.

J.

Dis. Child., 98:460,

1959.

24. Segal, S., and Martinek, H. : Transient

hy-potension in the etiology of hyaline

membrane disease. IX. International

Congress of Pediatrics, Montreal, 1959.

25. Desmond, M. M., Kay,

J.

L., and Megarity,

A. L. : The phase of “transitional

dis-tress” occurring in neonates in

associ-ation with prolonged postnatal umbilical

cord pulsations.

J.

Pediat., 55: 131, 1959.

26. Stahlman, M. T. : In Adaptation to

Extra-uterine Life, 31st Ross Conference on

(17)

1961;27;551

Pediatrics

and J. P. Hubbell

A. M. Rudolph, J. E. Drorbaugh, P. A. M. Auld, A. J. Rudolph, A. S. Nadas, C. A. Smith

Circulation in the Respiratory Distress Syndrome

STUDIES ON THE CIRCULATION IN THE NEONATAL PERIOD: The

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(18)

1961;27;551

Pediatrics

and J. P. Hubbell

A. M. Rudolph, J. E. Drorbaugh, P. A. M. Auld, A. J. Rudolph, A. S. Nadas, C. A. Smith

Circulation in the Respiratory Distress Syndrome

STUDIES ON THE CIRCULATION IN THE NEONATAL PERIOD: The

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