pediatrics 1961 rudolph 551 66

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 Childrens 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 CrippledChildren.

PRESENT ADDRESS: (A.M.R.) Department of Pediatrics, Albert Einstein College of Medicine, NewYork 61, New York.

551PEDIATRICS, April 1961

P ROFOUND cilangeS in the cardiovascularsystem occur in the newborn animal in

adaptation from a placental to a pulmonarycirculation. It is not unreasonable to expectthat occasionally the normal progression ofcirculatory changes may be disturbed. Thepossible role of such a disturbance of thecirculation in the production of the respira-tory distress syndrome (hyaline membranedisease) has been postulated.

Although intensive studies of the changesin the circulation after birth have beenmade in animals by Barclay et al.2 andDawes et a!. only limited information on

the changes in human infants is available.4The purpose of the present study is to

further delineate the changes in the circula-tion of infants with normal cardiovascularand pulmonary function and to determinewhether a circulatory disturbance may beresponsible for production of the syndromeof respiratory distress in certain newborninfants.

MATERIAL AND METHODSStudies of the circulation were conducted by

means of cardiac catheterization in 28 newborninfants. These infants were carefully observedfor evidence of respiratory distress, and wereseparated into three groups on the basis of theseverity and duration of respiratory signs.5Group I comprised 19 infants either with nosigns of respiratory distress or with mild eva-nesccnt symptoms. Four of these babies showedunquestionable evidence of mongolism, and

one was microcephalic. Eight of the 19 wereinfants of diabetic mothers. Their ages at thetime of cardiac catheterization ranged from 2to 34 hours and their weights from 2.414 to4.090 kg. Fourteen of these infants were malesand five females. (It is important to appreciatethat infants of diabetic mothers are heavier atthe same gestational ages than those born ofnondiabetic mothers.) Gestational ages of thesebabies ranged from 36 to 41 weeks. Themethod of delivery was by pelvic route in 14,and by cesarean section in five cases. Theclinical condition of all infants at the time ofdelivery and at the time of study was not re-markable.

All pressures were measured with the zeroreference level at the midchest level in the an-teroposterior diameter.

Group II consisted of nine infants with mildrespiratory distress. All these were infants ofdiabetic mothers. Four infants were males andfive, females. The ages at time of study variedfrom 2 to 11 hours, and weights were between2.073 and 3.181 kg. Their gestational ages atbirth were 33 to 39 weeks; two of the nineinfants were born by pelvic delivery and sevenby cesarean section. Seven of these babies wereconsidered to have mild respiratory symptoms,and two were thought to show moderate dis-tress. Group III included 10 infants with severerespiratory distress. Seven of these infants were

males and three, females. Five of this groupwere infants of diabetic mothers. Their agesat the time of catheterization were 3 to 21hours and weights were 1.278 to 2.869 kg. Thegestational age of these infants ranged from

30 to 37 weeks; six were born by pelvic de-

at Indonesia:AAP Sponsored on April 27, 2015pediatrics.aappublications.orgDownloaded from

552 RESPIRATORY DISTRESS SYNDROME

livery and four by cesarean section. These in-fants all had severe symptoms, and 8 of the 10died with increasing respiratory symptoms 3to 58 hours following the catheterization study.Necropsy confirmed the presence of severehyaline membrane disease in these infants.There was also no evidence to indicate thatthe catheterization procedure had contributedto 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 electrocardiographicstudies were carried out for all the infants withrespiratory symptoms and for the majority ofthose with no respiratory distress. The pro-cedure was performed after full discussion withand consent of at least one of the parents. Nomedicaments or anesthetics were administered.Oxygen therapy by inhalation was continuedduring catheterization in the 10 infants withsevere symptoms, all of whom were receivingoxygen before the procedure. The infantswithout symptoms, or with mild symptoms, didnot receive oxygen.

In 15 newborn infants cardiac catheteriza-tion was attempted by inserting the catheterinto the umbilical vein, wih the aim of manip-ulating it through the ductus venosus into theinferior vena cava and then into the heart. Inview of the tendency for the catheter to enterportal veins, with difficulty in maneuvering be-yond the ductus venosus, the attempt wasabandoned in five instances. In 10 infants, in-eluded in this report, the catheter could bemanipulated into the heart, but in only 2 ofthese was it possible to pass the catheter intothe pulmonary artery. In the remaining 28 in-fants, the catheter was inserted through theright saphenous vein in the groin. Under localprocaine anesthesia, a small incision was madejust below the groin and the saphenous veinwas 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. 3.5FLehman catheter was used in view of the smallsize of the vein.

After the catheter was passed into the rightatrium from the inferior vena cava, an immedi-ate attempt was made to enter the superiorvena cava. The catheter was then again with-drawn and manipulated into the right ventricle.A very careful continuous monitoring of theelectrocardiogram was then conducted with theaid 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 pulmonaryartery catheterized. In the other 16 instancesthe attempts to enter the pulmonary arterywere abandoned in view of the induction ofnumerous ectopic beats during these manipu-lations.

The catheter was also passed through theductus ateriosus in 20 of the 22 infants whosepulmonary artery was entered. As the tip ofthe catheter was manipulated beyond the pul-monary valve, it usually preferentially followeda course through the ductus arteniosus into thedescending aorta. In view of the relativelysmall size of the vessels, it was difficult to assesswhether the tip of the catheter was located inthe main pulmonary artery, in the ductusarteniosus itself, or in the aorta. Persistent at-tempts were therefore made to direct thecatheter into the left or right main pulmonaryartery. In the occasional instance in which thiswas not accomplished, the pulmonary arterialpressure and blood sample was obtained inthe main pulmonary artery just beyond thepulmonary valve.

The left atrium was entered in 27 infantsby passage of the catheter through the fora-men ovale. A pressure gradient between leftand right atrium was measured as the catheterwas withdrawn from the left to the right atrium.Cineangiography to establish the presence of aductal left-to-right shunt was performed inseven infants, by injection of 2 to 2.5 ml of75% sodium diatrizoate (Hypaque sodium) intothe left atrium.

The fluoroscopic examinations during manip-ulation of the catheter and the cineangiographywere performed with the aid of a 5-in. Philipsroentgen image intensffier. Pressures were con-tinually monitored with the use of a StathamP 23 D pressure transducer. Electrocardio-grams and pressures were recorded on a San-born direct-writing oscillograph. Oxygen satu-ration was measured by a spectrophotometricmethod.6

RESULTS

The hemodynamic observations in groupI, the 19 infants without significant respira-tory symptoms, are presented in Table I.One patient was studied both at 5 and 26hours of age. Right atrial pressures ranged


p33 Ui?4 Cl) Cl) C V

6

S6686

S

S6S

0

Cl)

0

3D

I.

0

z

0z

- a

3D

Sz

S0rIDz0

aa

CC.?

z

0a

H + + + + + + + +o!1t,;1

3,o7,r;sIT:w7nJ., 0 rIDO 0 -

. .. -

(% 70a)57?avdv3 zO ,, *, - t- o a - t- - t- w G C ; & .

- , *, *, - - , , I, , - - -

I

6,

: -. C.

- CC - C C C C 0 .,,; ,; 00

= 00 Xt- 006o 60 00

.

- o . Q C 00 00 . 00 i 00 i G O -p. .; t- ; w)00 t-t. -00 C CC Ct- t- 00 tt. 00 - t- 00 - t- Ct-

C 0 00 C 0 00 t- SO C P 0- t

= * t , ,, . X .. k 0 t- t- t.. C 6 t- t 00 t- t. t.. t.. t- t- 00 00 C t.. t- t- t-

C.)

Co

1-CO C vo 00 C OC *1t.. C 00 0 - t- * 00 t- 0- t- ) ) *it- C t- C C C t- 00 t- t- t- t- t- t- t- t- C C

*

E

0

S0 00 0 - 0 00 00 00 00 00 -P

C 00 00 0 C 00 00 000 00 00 00 00 * 00

,,, 0 00 00 00 00 00 00C C C C C t- 00 00

a,

, 0 0 0 00 00 00 1- 0 00P (0 -P W 00

00 0 0 0 0 00 00 00 5 000 - 00 00 00 -

0 00 0 t- 00 0 00 OtO 0 00C 00 C 00 00 00 C -P 00 C Si

I

00 00 00 0 .0 50 0- C 0 0 * G Si

I

, I0 C 0 S t.. 5) 5, 00 * 0 0

I

00 00 00 00 IS 0 Si 5 * S 0 00 0 00 0

I I I I I I

uopt4o 7v3u3.

0 . ! zz z z zzzzzzz z z

flJIanac7IIa C.) a a c a . . a

(oI)a8VlDu0i;07?D ; ; ; ? ;

iyofouo?ppuo 44 4 4 4 th4 4. . .! . . . 0 . 0 0 0 . . z : Z Z a: ZZZZZ

(0)1v81f1P 00 P 0 0 C 00 0 00 00 00 00 0 00 00 I 00 00 GD i 8 SSi 5, 5, S Si 5, S)G G #{149} 5,

(.n,)aDv 00 t- 0 C 00 0 Gi -P 00 00 00 Si - 00* 5, Si Si Gi Si

xIsHiai a4 Is i a a4 cz, , aOSISISfr cs

CSS8

8

SS

S.

C

S

6

SSCC

-C

4

0

.

S C. S

.

0 .6

.5;-

.. C

.

i.

lb 8S C

S

.5 .8-

.

r

Si 5, 5, C t- C 0 Si 5, C 00 0Si

ARTICLES 553



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 thanby 1.0 to 4.5 mm Hg except in two cases; inone the pressures were equal, and in theother right atrial pressure was 0.5 mm Hghigher. Right ventricular systolic pressureswere measured in 16 of these infants andranged from 33 to 80 mm Hg. Pulmonaryarterial systolic pressures ranged from 30 to68 mm Hg, with an average of 50.5. Pulmo-nary arterial diastolic pressures rangedfrom 8 to 42 mm Hg, with an average of24.5; the mean pressure ranged from 15 to49 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 to40 diastolic, with an average of 35.5 mmHg; and 38 to 51 mean pressure, with an av-erage of 45 mm Hg.

As shown in Table I, several infants hada small increase in saturation of blood atthe atrial level as compared to superior venacaval blood. This could represent someshunt through a foramen ovale, but itcould be due to addition of more fully satu-rated blood from the inferior vena cava, assuggested in one instance. Since the majorinterest in these studies was in connectionwith the ductus arteriosus, calculations ofpulmonary to systemic flow ratio were madeusing right ventricular samples for mixedvenous saturations, and thus the pulmonaryto systemic flows presented in Tables I, IIand III actually reflect the size of the ductalshunt.

In the eight infants for whom it was pos-sible to obtain reliable saturation data fromthe pulmonary artery, there was no evi-dence of any significant difference in oxy-gen saturation between right ventricle andpulmonary artery, indicating the absence ofany significant left-to-right shunt throughthe ductus arteriosus in four. A very smallleft-to-right shunt through the ductus wasevident in the other four, with a calculatedpulmonary to systemic flow ratio varyingfrom 1.2:1 to 1.6:1.

Oxygen saturation in the systemic arteryranged from 75 to 96%. In three instances,the arterial saturation was somewhat less

than the left atrial saturation, suggestingthe presence of a small right-to-left shunt,probably at the ductal level. In one in-stance, the left atrial saturation was lessthan pulmonary venous saturation, suggest-ing a right-to-left atrial shunt. Left atrialblood samples showed saturations above 90%in all except two infants, in whom the satura-tions were 80 and 82% respectively. In one ofthese a pulmonary venous sample showed asaturation of 91%, indicating some right-to-left shunt. The possibility of a disturbanceof a ventilation perfusion ratio as a cause ofunsaturation in some of these infants shouldalso be considered.

Table II presents the hemodynamic datain the nine infants in Group II with mildrespiratory symptoms.

Right atrial pressures in this groupranged from - 2.0 to + 8 mm Hg and leftatrial pressures from - 0.5 to 9 mm Hg.There was a left-to-right atrial pressuregradient in all, ranging from 0.5 to 6.5 mmHg. Right ventricular systolic pressureranged from 45 to 85 mm Hg. Pulmonaryarterial pressure was measured in eight ofthe 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 37.2mm Hg. Systemic arterial pressures rangedfrom 48 to 100, with an average of 65.2 mmHg in systole, and from 22 to 63, with anaverage of 41 mm Hg in diastole; meansystemic pressures ranged from 35 to 76,with an average of 51.5 mm Hg.

Oxygen saturation data indicated thepresence of a small left-to-right shunt at theatrial level in two infants, in whom the rightatrial saturation was 5 to 8%, and 12% higherthan caval saturation, respectively. It is ofinterest that these two infants had thelargest pressure gradients between left andright atria, measuring 5 and 6.5 mm Hg re-spectively. Adequate sampling from thepulmonary artery was possible in eight ofthe nine infants. In four there was no dif-ference in saturation between right ventri-cle and pulmonary artery, and in the otherfour there was only a small increase in oxy-gen saturation at the pulmonary arterial


73?UJUZI4 rID C

ARTICLES

C &D CI) Cl) CI? CC Cl)

enPna Ut l1;v3 + + + + + + + +

o7v3JSiO7i :vqnj

0 0 Si 0 Si . ,. .. .. , ,

aF3D

aCF

aI.

-3

aF

rID

4 z

SC3Dz0F

a3Da

CC.?

a

z

Ca

(% lorI) fi;wvdv3ij-

t- P - - 0 t-

Si Si Si - - -

C

I

-

Si 6 0 C#{149} CS 00 00

C

C 1 .I I I S.; . C 005) 00t- 005) 0000 -00 00 0000 0000 0 0000

iX t-Si #{149}00#{149}t- 0000 C .SiSi 00- -PS, tCXC 5, C SiOSi Si00t- 0000 t-t-t-t- 00 t-t- CC) t-Ct- 00

;; ; ;; ; ; ; ; ;

C.)

C/)

t-- 5, 000 5, SiSi 5 F-

0,; -P S t . t F- F. F. C 00 F. F- F. 00 00 00 C F-

E

C

C .

- 00 0 00 00 Si 0 Si6 00 F. 00 t-

0 Si Si Si 00 00 C SiSi Si C Si 00 00

6,

S

; ? :; ?

00 i 00 F- 53 5, 0 0Si Si Si Si Si Si Si Si

00 0 0 0 5) 0 0 00 C 00 00 C

- 0

& z: : 0 0 00 F- 53 0 00 00 00C 00 C 00 00 00 C -P

-

00 00 00

00 - Si - C Si

s3

00 00 00 00

t 0 Si 0 t- Si

0 0 0 0 Si Si C 0 Si 0

(.7Ji) ?DV ;znioz;D;t?9

:s c C) C.) Q c. c) C_)

:; i

.s.iqjoj#{231}foUOI!PFLOJ 4 4 4 4 4 4 4 4 4.5 . . . . . . .5 .

(l);yttlfl E (Iv)15v C 00 F- Si Si 00 P

ZI5 a. S S a

555

S

.0SE- .8 >

. I- Si Si P 00 C F- 00



level, indicating the presence of a small left-to-right shunt through the ductus arteriosus.The ratios of pulmonary to systemic flowswere 1.2:1 to 1.6:1 in these four babies.

Systemic arterial oxygen saturationranged 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 wasslightly lower than that in left atrium, mdi-eating the presence of a small right-to-leftshunt through the ductus arteniosus. Leftatrial saturation, where measured, was 90%or above, in all but two instances. In thesetwo babies it was 85 and 86% respectively.

The hemodynamic observations on the10 infants in Group III are presented inTable III.

Right atrial pressures ranged from - 6.5to 0 mm Hg and left atrial pressures from- 5.5 to 6-9 mm Hg. The pressure gradients

from left to right atrium ranged from 1 to6-9 mm Hg. Right ventricular systolic pres-sures ranged from 25 to 35 mm Hg. Pulmo-nary arterial pressure was measured in7 of the 10 infants. Pulmonary arterial

systolic pressures ranged from 23 to 52 mmHg, with an average of 38.5; diastolic pres-sures varied between 9 and 30 mm Hg, withan average of 19 mm Hg; mean pulmonaryartery pressures were 16 to 40, with an aver-age of 26.5 mm Hg. Systemic arterial pres-sure was recorded in six infants; systolicpressure varied from 29 to 60, with an aver-age of 46 mm Hg; diastolic pressure from16 to 35, with an average of 28.5 mm. Hg;and mean pressure from 20 to 45, with anaverage of 36 mm Hg.

In all these cases oxygen saturation datawere obtained while the infants werebreathing 100% oxygen, administered by aloosely-fitting mask. A significant increasein oxygen saturation of 34 and 11% respec-tively was noted between superior vena cavaand right atrium in two infants, indicatingthe presence of a left-to-right shunt throughthe atrial septum. A further increase in satu-ration was noted in one of these infants atthe ventricular level, possibly due to astreaming effect. No congenital cardiacanomalies were demonstrated in those stud-

ied at necropsy. Oxygen saturation wasmeasured in the pulmonary artery in seveninfants. An increase in oxygen saturation of4 to 19% was noted at the pulmonary arterylevel. The actual size of the left-to-rightshunt through the ductiis was difficult toestimate accurately, since there was also aright-to-left shunt in some instances. How-ever, a very large left-to-right shunt throughthe ductus arteriosus was present in allseven infants in whom this could be esti-mated. Systemic arterial oxygen saturationin the descending aorta (during oxygenadministration) ranged from 63 to 98%. Theinfant with the lowest saturation of 63% hada low left atrial saturation (80%) and a verylarge right-to-left shunt through the ductusarteriosus. The left atrial saturation in theother five infants in which it was measured,was above 90%.

A comparison of the hemodynamic datafrom these three groups of patients indicatesthat there is essentially no difference be-tween infants with no respiratory distressand those with mild respiratory distress.Their average pulmonary arterial pressures,systemic arterial pressures and left and rightatrial pressures are quite similar. Aboutone-half of each group had no ductal left-to-right shunt, and the others had only smallleft-to-right shunts through the ductus withpulmonary to systemic flow ratios 1.6: 1 orless in all instances. The infants with severerespiratory distress differed considerablyfrom the other two groups. The average pul-monary arterial pressures were lower, andthe average mean pulmonary arterial pres-sure was about 10 mm Hg lower than in theother groups. The systemic arterial systolicand diastolic pressures were also lower, andthe average mean systemic arterial pressurewas about 10 mm Hg lower than in the nor-mal and mildly distressed group. The groupwith 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-leftshunt.

In view of the great diversity of these in-fants with regard to period after birth whenstudied, weight, gestational age and mode


0 . . .

.

u9o!o;o+ + + + + + + + +

pIt-) ulrI4

,npna UI .q763

Cl) Cl) CI) Cl) Cl) Cl) CI) Cl) Cl)

+ + + + + +

01pJ.liohi ;tIT :uqn,j I it I I 11 1 j3 53 53 S S

(% ?oa) IDzavdv3 o t- Si - 0 00 P Si 0- - - Si Si

C#{149}0

6,

C 0.

000 00

Si 00 00 P 00 0. . . . .

0 Si 00 P00 0

C

I #{176} Si 00tC SiP Si0 5) Fr- F-t-t- 0000 00 0

6,

-. 0 0 I000 000 00 00 00 PSi 5)F- C F- C 00 0 00 0 0 00

t- t-t I F. Si 0 00 Si C P 0 F- . 0 F- 00 000 00 00 F- F. F- F- F. t. 0 00 00 F. F-

P 5) 0 00 00 Si 0 5) Si. . . . . . . .

5i 00 Si C C 0 5) 0 00C 6 C F- F- 0 00 F- 00

C.).

C)

0 F- 0 00 C

G . C C Si C 00 F-

%

6 !.

S

E

.

S

0 0 00 Si F- SiSi P Si Si P

0 0 F- 5) 00Si Si Si D) Si

Si 0 0Si P 00 00 00

65

S

-

S

00 00 0 00 00 F-- 5i Si Si Si

z - 00 00 05) Si Si - -

Si 0 Si 0 . 5,Si P 00 5) P P 00

.

0 5) 0 Si Si 0 Si F- 0 F- -,- -- -- -.- S-0 00 0 F- 0 Si 00 00 00Si 00 .0 Si P 00 5) 00 Si Si

S

0

- - Si Si 5,

.

5, 0

F; - 0 00 0I I

.,

5) Si Si 0 0 00I I I I

ILS54173q ci, C.) C_) C_) , , a . C..? C..

(n)a6V7vuolv1s? Si F- 00 Si Si 0 F- SiSi 5) Si Si Si Si 5) 00 Si 5.

LIYloJc!otiot;.lPuod . 4 4 4 S S C.. . . S !

. C.;

(#{244}) ;y5u0 00 - P 0 F- 00 Si 00

00 F- Si Si C Si 00 F-00 C C P Si F-

- Si Si - Si Si Si

(.iy)aDy Si Si 5) - C 0 Si Si- Si - -

X? a. a4

Si 5,

.0

C

0

8

P 00 00 F- 00 0 0

ARTICLES 557



TABLE IV

ANALYSIS OF AGE, WEIGHT, GF.STATIONAL AGE AND MODE OF DELIVERY IN INFANTS WITH AND WITHOUTRESPIRATORY DISTRESS*

Cases(no.)

Average Gest.Age

Average Wt.(Ib)

Average Age(hr)

CaesarianSection

,

#{149} . t

Normal

Mild distressSevere distress

8

8

8

37.3

35.8

34 . S

7.5

6.5

5 . 4

18.0

5.4

8 .0

6

5

4

8

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 inexplaining the striking hemodynamic dif-ference in the infants with severe respira-tory distress. At first analysis (Table IV) itdid not appear that any of these factorswere significant, as there was considerableoverlap in each group. However, a morecomplete analysis produced some interest-ing observations.

A graph, not shown, relating pulmonaryarterial systolic or mean pressure to age inhours at the time of study indicated that

there is a tendency for the pressure to de-crease gradually after birth. The severelydistressed infants had pressures consider-ably lower than the other two groups. Inorder to plot a larger number of patients,right ventricular systolic pressure was re-lated to age, as shown in Figure 1. Thisdemonstrates a suggestive decrease of pres-sure with age with a linear regressionof y = - 0.227x + 58 for the normal andmildly distressed groups, whereas the se-verely distressed infants had lower pressuresat the same age, with a linear regression ofy = -0.45x + 45.

When right ventricular systolic pressureis plotted against the weight of the infants(Fig. 2) it is demonstrated that the largerthe infant, the higher is the right ventricularsystolic pressure. Also, although there issome overlap, it is apparent that the se-verely distressed infants were smaller infantsand it is possible that the lower right yen-tricular and pulmonary arterial pressureswere related to this factor rather than to the

fact that they had the respiratory distresssyndrome. The linear regression for allgroups is represented by y 8.2x + 26.

The relationship of right ventricular sys-tolic pressure to gestational age is similar tothat 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 werethose with severe respiratory distress, sothat it is not possible to separate the role ofmaturity and that of the distress syndrome inrelationship to the lower right ventricularsystolic pressures.

An evaluation of the relationship be-tween age of the infants, gestational ageand 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 theinfants weight, age and gestational age.The difference in oxygen saturation doesnot truly represent the size of the left-to-right shunt, as this depends also on the ac-tual level of saturation in mixed venousblood.7 The presence of large left-to-rightshunts in the distressed infants is againshown, and although there is no definite re-lationship to age, weight or gestational age,it appears that large shunts are commonerin the immature infants.

The cineangiographic studies confirmedthe presence of a small ductal shunt inthree infants with a small calculated shunt,showed no shunt in three infants in whom


070

60

50

40

30

0o.0

0

.

0

00

0

0

0

0

0 0

0

00

0

0 00 0 0

00 0

0.

S

5 0 5

AGE HOURS

0

0

0

I0

C 20 25 30

Hz

80

20

ARTICLES

0 .JJ4Qa

0 N0i& + MLD. SEVERE

559

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

no ductal shunt was found by saturationdata, and demonstrated a very large shuntin one of the severely distressed infants.

DISCUSSION

Hemodynamic Changes in the NormalInfant after Birth

Circulatory adjustments to extrauterinelife are not completed within the first fewminutes after birth but are extended overseveral hours and possibly several 8The available information regarding thehemodynamic status of the infant with nor-mal circulatory and pulmonary systems inthe first 24 hours of life is very meager.4

The elegant studies of Dawes3 in fetallambs have demonstrated that ventilationof the lungs decreases pulmonary vascularresistance and thus results in a great in-crease in pulmonary blood flow. Associatedwith this decrease of pulmonary vascularresistance, there is a reversal of the flowthrough the patent ductus arteriosus fromthe fetal right-to-left direction, to providea left-to-right shunt. This left-to-right shuntthrough the ductus arteriosus has beenshown to persist in the fetal lamb for atleast several hours after ventilation of thelungs and possibly aids in increasing sys-temic arterial saturation when the lungs areunevenly expanded.#{176}


80

70

60

50

40

30

20

0

I.?

0

0

S

0

0 0 0

0

00

0

0S 0

0 S 0.1

0 0 0

0S

80

S

0 NORMA10 FvILDS SEVERE. NORMAL, MILD

AND SEVERE

S

0

40 2

WEHT KILOGRAMS

3


0

.

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

The presence of a ductal left-to-rghtshunt in normal newborn infants was firstinferred from dye dilution studies by Precand Cassels1#{176}and also by cardiac catheteri-zation studies by Adams and Lind4 andRowe and James.8 The physiologic studiesof Adams and Lind suggested that there isa very large ductal left-to-right shunt inthe normal newborn infant. Analysis of theirdata suggests, however, that in three of theeight babies studied, the catheter was in theductus or aorta when the pulmonary ar-tenial sample was obtained, in two the datawere inadequate, in one there was no ductalshunt, in one the shunt was minimal and inthe remaining infant there was a rise in oxy-

gen content of 2.8 vol % in right ventricularblood as compared to right atrial blood, anda further rise of 3.3 vol % in pulmonaryarterial blood. Although this appears to rep-resent a large ductal shunt, the data are dif-ficult to evaluate.

The data in the present study indicatethat the ductus is functionally closed, al-though anatomically patent, in many nor-ma! infants in the first day of life. In someinfants, a small left-to-right shunt occursthrough the ductus, with a pulmonary tosystemic flow ratio of 1.6 : 1 or less. Asshown in Figure 4, none of the infants over15 to 20 hours of age with normal cardio-vascular systems showed a rise of oxygen


ARTICLES 561

80

870

0

0

60 0 0 0 000

0S 0

50 0 0

a . 0 0S 0

40 0 5 0S

0 0

30 S 0

SS

20 0 N0fV1ALa MLDS SEVERE

0

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

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

20#{149}

.

0 NORMAL0 MLD. SEVERE

15Li

aj: 10o#{149}o

5

ci 000 0

0 0 00 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 venousblood (RV) to age of infants.



20 0 NORMAL0 MILD

S . SEVERE

.

5S

#{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 KS GROUP

0

0

a 00

0

.

0

0

S

S

0

0

000

U-.U-0

0c0 - I

0a:

Fic. 5. Relationship of difference in oxygen saturation between pulmonary artery (PA) and mixed venousblood (MV) to weight of infant.

saturation in the pulmonary artery ofgreater than 2%. The difference in thesefindings as compared to those of Adamsand Lind4 and Rowe and James8 may be re-lated to the fact that no premedication wasemployed in our studies. It is also interestingthat in the studies of Rowe and James the

youngest infant, aged 2 days, had no demon-strable ductal shunt, whereas five infantsbetween 5 and 11 days had evidences of ashunt. These findings, and those of El-dnidge et al.1 indicate that the ductus maybe 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 venousblood to gestational age of infant.


ARTICLES 563

providing physiologic confirmation of theanatomical studies of Mitchell.12 The pres-ent observations also corroborate the aus-cultatory evidences of patent ductus arteri-osus demonstrated by Burnard,13 and byBraudo and Rowe.14 The murmur of patentductus arteriosus was noted to be muchcommoner by these authors in the first 10hours of life and was quite unusual beyondthis age.

The pulmonary arterial pressure variedgreatly in the first day of life. In some in-fants it had dropped very rapidly, almost toadult levels, within a few hours, whereas inothers, the pulmonary arterial pressure wasstill close to systemic levels at the end ofthe first day. There was, however, a sugges-tion of a gradual decrease in right ventricu-lar and pulmonary pressure during the firstday. The height of the pulmonary arterialpressure was in no way related to the pres-ence or absence of a ductal shunt in thenormal or mildly distressed infants. It ap-peared that the factors determining thepresence of a left-to-right shunt were notonly a decrease in pulmonary vascular re-

sistance, but the degree of ductal constric-tion.

Hemodynamic Observations in Infantswith Severe Respiratory Distress

The infants with severe respiratory dis-tress showed definite differences in their cir-culatory status as compared to the normaland mildly distressed infants. Their sys-temic arterial and pulmonary arterial pres-sures were considerably lower; they all hada widely patent ductus arteriosus with alarge left-to-right shunt and in many instan-ces a right-to-left shunt through the ductus.A preliminary report of some of these datahas been presented,#{176} and first analysis sug-gested that all the circulatory phenomenawere associated with the respiratory distresssyndrome. A more complete analysis hasindicated, however, that although the lowersystemic and pulmonary arterial blood pres-

0 Society for Pediatric Research, Buck Hill Falls,May, 1959.

sure may be related to the severe respiratorydistress, it is also possible that prematurityor immaturity may explain these differences.The infants with severe respiratory distresswere smaller and of lower gestational agethan the normal and mildly distressed in-fants. In order to establish the possible rela-tionship of low pulmonary and systemicarterial blood pressures to the respiratorydistress syndrome, it will be necessary toprocure a great deal more information ininfants of comparable age, weight and ges-tational age.

The association of a widely patent ductusarteriosus with severe respiratory distressappears to be possibly related to the dis-ease, but it could be related to immaturity.In view of the small numbers of infantsstudied, of the variation in circulatory ad-justment after birth, and of possible differ-ences in the response of the ductus in thepremature infant, the significance of thisobservation cannot be accurately evaluatedat 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 suggestedthat the ductus may be patent in theseinfants.

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 beresponsible for the disease. A widely patentductus arteriosus may produce an excessiveload on the left ventricle, with the featuresof left ventricular failure in early infancy.The possible relationship of cardiac failureto the development of the respiratory distresssyndrome has been suggested by Lendrumand Shanklin,16 who found in a series ofnecropsies in the neonatal period that, inthe presence of what seems to be a physio-logically deficient left ventricle, 90% of thesecases showed hyaline membrane.

The hyaline membrane found in thelungs of infants dying of the respiratorydistress syndrome has been demonstratedby Gitlin and Craig17 and Lynch and Mel-br18 to contain fibrin derived from the in-



fants blood proteins. Although Landing19has not found a close association betweenthe presence of hyaline membranes and pul-monary edema, Lynch2#{176}in his experimentalstudies 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 inaffected infants, and in some instances pul-monary edema has been the most strikingpathologic finding.

The presence of pulmonary edema andthe possible relationship to cardiac failurehas suggested the possible implication ofthe 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 enlargedand, if the infant recovers, undergoes arapid reduction of size, adding further sup-port to the possibility of presence of car-diac failure. He has also indicated thatheart murmurs are commoner in infantswith respiratory distress than in normalinfants5

The objection may be raised that pul-monary edema in adults usually does notdevelop until pulmonary venous and leftatrial pressure are elevated to a level of 25mm Hg. The left atrial pressures in theinfants with severe respiratory distress werenot significantly elevated, and this raisessome doubts regarding the role of left yen-tricular failure. The capillaries of infantsmay, however, be more permeable thanadult vessels, and evidence of left ventricu-lar failure has been observed in infantswith congenital heart disease, with left at-rial pressures of 10 to 15 mm Hg. It is alsoimportant to appreciate that transmuralpressure is most significant; in infants withrespiratory distress, the intrapleural pres-sure may reach high negative levels, andthus the effective left atrial, pulmonaryvenous, and transmural pressuies may beconsiderably elevated.

Thus a considerable amount of evidencehas been accumulated to implicate a widelypatent 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 arterialblood pressures indicated the possibilitythat infants with severe respiratory dis-tress may have generalized vasodilation or,rather, lack of vasoconstrictor response.Measurements of systemic arterial pressureby indirect od24 indicate that theblood pressure in these infants is low soonafter birth and that it remains low unlessrecovery ensues. Although there is a markeddecrease of pulmonary vascular resistanceaccompanying the ventilatory process, thepulmonary vessels maintain a state of vaso-constrictor tone at least for several hoursafter birth normally, as shown by the per-sistence of a high pulmonary arterial pres-sure. Inability of the pulmonary vessels tomaintain this vasoconstriction may allow fora very large left-to-right shunt in the pres-ence of a patent ductus. Furthermore, it ispossible that the ductus arteriosus itself mayalso not undergo its normal constriction, be-cause of the same generalized lack of vaso-constrictor tone. The prolonged pulsationsof the umbilical arteries observed in infantswith distress may similarly be related to lackof umbilical vessel constriction.25 The causeof the poor vasoconstrictor response pre-sented in this hypothesis is not known,but it could be related to immaturity of thevasomotor response systems.

Third, the possibility that the large left-to-right shunt through the ductus may be oc-casioned by severe respiratory distresscertainly has to be entertained. It seemsunlikely that the response of the ductusarteriosus itself can be affected by a highnegative intrathoracic pressure, since thevessel has a thick muscular wall. However,the large negative pressures developedcould possibly increase the size of the shuntthrough a ductus which is partially patent,by opening up small pulmonary blood yes-sels. But, as has been shown by Daweset al., alveolar expansion is necessary todecrease pulmonary vascular resistance;and since the lungs in the respiratory dis-tress syndrome are not usually well ex-


ARTICLES 565

panded, it is not very likely that this mecha-nism is responsible for the large ductalshunt.

CONCLUSIONS

The studies on the circulatory status ofnormal infants in the neonatal period havedemonstrated that the pulmonary arterialblood pressure remains elevated for at leastseveral hours after birth and graduallydrops to near adult levels within hours ora few days. The pressure level appears tobe related to gestational age and birthweight, being higher in mature infants.

The ductus arteriosus gradually closesafter birth in normal newborn infants, buta 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 mayreopen under appropriate stimuli duringthe first 7 to 10 days of infancy.

Studies of infants with severe respiratorydistress syndrome (hyaline membrane dis-ease) revealed pulmonary arterial pressureslower than in infants with normal circu-lation, but since these infants were smallerand less mature, the significance of thisfinding could not be evaluated.

All infants with severe respiratory dis-tress syndrome also had evidences of awidely patent ductus arteriosus with a largeleft-to-right shunt. In the small number ofbabies studied, this finding did not appearto 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 withthe respiratory distress syndrome could bemade on the basis of the present study.The possible role of the widely patentductus arteriosus as a cause of left ventricu-lar failure, pulmonary edema, the respira-tory distress and hyaline membrane forma-tion is considered. The alternate hypothesisthat there is a generalized lack of vasocon-striction possibly related to prematurity,affecting systemic and pulmonary bloodvessels as well as the ductus arteriosus, isalso presented. Obviously no far reaching

therapeutic conclusions in regard to hyalinemembrane disease can be reached on thebasis of the limited information presented.Nevertheless, it seems fair to say thatserious consideration should be given toattacking the respiratory distress syndromefrom the circulatory view point. The use ofdigitalis has been repeatedly suggested, andgood results have been claimed.26

SUMMARY

Hemodynamic measurements by meansof cardiac catheterization were obtained in38 infants in the first 30 hours after birth.Nineteen of these infants were consideredto have normal circulatory and respiratorysystems. Nine had mild respiratory distress,and 10 had severe respiratory distress.

The circulatory systems of infants withmild respiratory distress did not appreci-ably differ from the normal. Some infantsin both these groups showed evidences ofpatency of the ductus arteriosus with asmall left-to-right shunt for the first 10 to15 hours after birth.

The infants with severe respiratory dis-stress had widely patent ducti, with largeleft-to-right shunts and, in some instances,right-to-left shunts. The pulmonary arterialand systemic arterial pressures were lowerin these infants as compared to the normaland 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 prematurityalone.

The possible role of left ventricular fail-ure associated with a large left-to-rightductal shunt is discussed. A generalizedlack of vasoconstrictor tone could possiblybe responsible for systemic and pulmonaryarterial hypotension as well as for the widelypatent ductus arteriosus.

REFERENCES

1. Lendrum, F. C. : The pulmonary hyalinemembrane as a manifestation of heartfailure in the newborn infant. J. Pediat.,47:149, 1955.

2. Barclay, A. E., Franklin, K. J., and Pntch-



ard, M. M. L. : The Foetal Circulation.Oxford, Blackwell, 1944.

3. Dawes, G. S., et al.: Changes in the lungsof the newborn Iamb. J. Physiol., 121:141, 1953.

4. Adams, F. H., and Lind, J. : Physiologicstudies on the cardiovascular status ofnormal newborn infants (with specialreference to the ductus arteriosus). PEDI-ATRICS, 19:431, 1957.

5. Drorbaugh, J. E., et al.: Clinical observa-tions on the cardiopulmonary status ofinfants with hyaline membrane disease.J. Dis. Child. 98:145, 1959.

6. Gordy, E., and Drabkin, D. L. : Spectro-photometric studies. XIV. Determinationof oxygen saturation of blood by a sim-plified technique applicable to standardequipment. 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 normalpulmonary arterial pressure during thefirst year of life. J. Pediat., 51 : 1, 1957.

9. Born, G. V. R., et a!.: The relief of centralcyanosis 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 ofthe ductus arteriosus in newborn in-fants : a preliminary report. Science,119:731, 1954.

12. Mitchell, S. C. : The ductus arteriosus inthe neonatal period. J. Pediat., 51:12,1957.

13. Burnard, E. D. : A murmur from the ductusarteriosus in the newborn baby. Brit.Med. J., 1:860, 1958.

14. Braudo, M., and Rowe, R. D. : Quoted byRowe, R. D., in Adaptation to extra-uterine life, 31st Ross Conference onPediatric Research, p. 38.

15. Burnard, E. D. : The cardiac murmur inrelation to symptoms in the newborn.Brit. Med. J.,1:134, 1939.

16. Shanklin, D. R. : Cardiovascular factors indevelopment of pulmonary hyalinemembrane. Arch. Path., 68:49, 1959.

17. Gitlin, D., and Craig, J. M. : Nature ofhyaline membrane in asphyxia of new-born. PEDIATJIICS, 17:64, 1956.

18. Lynch, M. J. G., and Mellor, L. D. : Hy-aline membrane disease of prematurelungs. J. Pediat., 47:275, 1955.

19. Landing, B. H. : Pathologic features ofrespiratory 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 inthe dyspneic newborn baby. Brit. Med.J.,1:1495, 1959.

23. Neligan, G. A. : The systolic blood pressurein neonatal asphyxia and the respiratorydistress syndrome. J. Dis. Child., 98:460,1959.

24. Segal, S., and Martinek, H. : Transient hy-potension in the etiology of hyalinemembrane disease. IX. InternationalCongress 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 umbilicalcord pulsations. J. Pediat., 55: 131, 1959.

26. Stahlman, M. T. : In Adaptation to Extra-uterine Life, 31st Ross Conference onPediatric Research, p. 92.


1961;27;551Pediatricsand J. P. Hubbell

A. M. Rudolph, J. E. Drorbaugh, P. A. M. Auld, A. J. Rudolph, A. S. Nadas, C. A. SmithCirculation in the Respiratory Distress Syndrome

STUDIES ON THE CIRCULATION IN THE NEONATAL PERIOD: The

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/27/4/551including high resolution figures, can be found at:

Citations http://pediatrics.aappublications.org/content/27/4/551#related-urls

This article has been cited by 6 HighWire-hosted articles:

Permissions & Licensing

http://pediatrics.aappublications.org/site/misc/Permissions.xhtmlor in its entirety can be found online at: Information about reproducing this article in parts (figures, tables)

Reprints http://pediatrics.aappublications.org/site/misc/reprints.xhtml

Information about ordering reprints can be found online:

Online ISSN: 1098-4275.Copyright 1961 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007.has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it


1961;27;551Pediatricsand J. P. Hubbell

A. M. Rudolph, J. E. Drorbaugh, P. A. M. Auld, A. J. Rudolph, A. S. Nadas, C. A. SmithCirculation in the Respiratory Distress Syndrome

STUDIES ON THE CIRCULATION IN THE NEONATAL PERIOD: The

http://pediatrics.aappublications.org/content/27/4/551the World Wide Web at:

The online version of this article, along with updated information and services, is located on

ISSN: 0031-4005. Online ISSN: 1098-4275.PrintIllinois, 60007. Copyright 1961 by the American Academy of Pediatrics. All rights reserved.

by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication,


pediatrics 1961 rudolph 551 66

Documents

human infants

infants ofdiabetic mothers

respiratory distress

mildrespiratory distress

gestational ages atbirth

department of pediatrics

present study

ofnondiabetic mothers