Factors controlling pulmonary vascular resistance in fetal lambs

568

T h e ] o u r n a l o[ P E D I A T R I C S

Factors controlling pulmonary vascular resistance in fetal lambs A series o[ experiments measuring pulmonary vascular resistance in the [etal lamb revealed that spontaneous changes in resistance occur in the unexpanded [etal lung; expansion o[ the [etal lung with a gas mixture that produces no significant alteration in arterial pO~ or pCO: results in a marked [all in pulmonary vascular resistance; expansion o[ [etal lungs with deoxygenated dextran in saline produces only a small [all in pulmonary vascular resistance; inflation of [etal lungs with oxygenated dextran in saline and arterial blood produces a marked Jail in vascular resistance; the [all in pulmonary vascular resistance with air inflation o[ the [etal lung cannot be ablated by vagotomy, atropinization, or administration o/ismeline.

R. M. Lauer, M.D., * J. A. Evans, M.D., H. Aoki, M.D., and C. F. Kittle, M.D. KANSAS

CITY~

KAN.

S E V E R A L F A C T O R S have been shown to alter pulmonaw vascular resistance in the adult mammalian hmg. These include changes in pulmonary vasomotor tone as influenced by neurogenic factors,: hypoxia,: and hypercapniaa; and mechanical factors such as back pressure from the left atrium or puhnonary veins, increase in pulmonary blood flow, and opening of pulmonaryarterial communications2 In the fetus the pulmonary vascular resistance, although variable, is at a high level, such that only about 12 per cent of the sys-

From the Departments o[ Pediatrics, Physiology, and Surgery, University o/Kansas, School o[ Medicine. Supported by Research Grants HD-00250-02 o[ the National Institute o[ Child Health and Human Development and HE-04392 o[ the National Heart Institute, United States Public Health Service. *Address, University ol Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, Kan. 66103.

temic venous return passes through the hmgs. The remainder passes through the foramen ovale and the ductus arteriosus, a The initial expansion of fetal lungs results in a marked decrease in pulmonary vascular resistance with a marked increase in pulmonary blood flow2 This has been shown to occur following inflation with air, oxygen, or nitrogen, ~' s but not after inflation with a saline solution, r The mechanical effect of uncoiling of arterioles of the lung has been suggested as a cause of the fall in the pulmonary vascular resistance with the initial expansion of the fetal lung, ~ as has alteration in vasomotor tone. s' :0 This investigation was undertaken to determine if pulmonary vascular resistance is stable in the unexpanded fetal lung; how resistance is affected by expanson of the hmgs with a gas mixture similar in content to the blood gases: whether or not there is a difference in the change in pulmonary vaseu-

Volume 67 Number 4

Pulmonary vascular resistance in [etal lambs

lar resistance when deoxygenated or oxygenated fluids are used to expand the lungs; and whether or not the fall in pulmonary resistance is mediated through adrenergic or cholinergic nerves. MATERIAL

AND METHODS

Twenty-one lambs from pregnant Western ewes were studied. All ewes were considered to be near term by an experienced sheep herder and veterinarian. The ewes, weighing from 110 to 115 pounds, were anesthetized with thiopental (250 to 350 rag.). The tracheas were intubated following the administration of intravenous succinylcholine (100 mg.). Ventilation was controlled with a custom-made ventilator with adjustable rate and depth. Maintenance anesthesia was provided by nitrous oxide, 4 L. per minute, delivered into a standard anesthetic circle system with oxygen, 2 L. per minute, and carbon dioxide absorption. Relaxation for the maternal cesarean hysterotomy was provided with D-tubocurarine (30 to 50 mg.). The lambs were given D-tuboeurarine (1 to 2 mg.) intramuscularly through the uterine wall prior to their delivery by cesarean section. Immediately following birth a rubber glove filled with warm saline solution was tied over the lamb's head to prevent the inspiration of air. The lambs were placed on their backs alongside their mothers, still attached by their umbilical cords. They were surrounded by electric heating pads to maintain their temperature as near that of the ewes' as possible. Maternal and fetal rectal temperatures were recorded by thermistor probes. Thoracotomy was performed on the lamb through a midline sternal splitting incision. The right lower pulmonary artery was isolated and surrounded by No. 2-0 silk. The thread ends were passed through a short length of polyethylene tubing so that flow could be occluded for zero reference of the flow probe. A small, previously calibrated, implantable type electromagnetic flow probe* was placed around this vessel. The ~Carolina Medical Electronics Corp.

569

right upper pulmonary artery, the left atrium, and the right femoral artery were cannulated for pressure recording and blood sampling. Pressures were recorded with P 23-A Statham gauges in the puhnonary artery and femoral artery, and with a PR 2356-300 Statham gauge in the left atrium on a four-channel Sanborn direct writing oscillograph. Samples of blood were collected in rapid sequence from the pulmonary artery, left atrium, and femoral artery during various experiments. The pOz, pCO2, and p H of these samples were measured by an electrode assembly* at a temperature equal to the animals' rectal temperatures. When the blood specimens could not be analyzed immediately, the three samples were placed in an ice bath until they could be processed. The blood drawn for analysis from the lamb was immediately replaced by fresh heparinized blood obtained from the maternal femoral artery. A tracheotomy was performed on the lamb, and a saline-filled corked tube was inserted. The lungs were expanded and rhythmically ventilated by manual compression of an anesthetic bag filled with various gases or by manual compression of a 100 c.c. syringe filled with various fluids. RESULTS Control period. Table I shows the condition of each preparation at the end of the control period. The ewes varied considerably in their arterial pOz, pCO~, and pH. Comparing these data to those published for standing unanesthetized ewes, 11 the mothers of lambs 2, 8, 11, 13, and 16 were acidotic and the ewe for the eleventh lamb was also hypercarbic. Despite efforts to maintain maternal and fetal temperatures at an equal constant level, a temperature gradient between ewe and lamb often resulted. Thus, these preparations cannot be considered to mirror the normal intrauterine state, in which fetal and maternal temperature are equal. Following delivery of the lambs and surgical preparations, a period varying from *Instromentatlon Laboratories, Inc.

570

Lauer ct al.

October 1965

Table I Fetus ! ! L

Rectal I tern-

Pulmonary artery ;0, pCO~

Left atrium pCO~ (l?lm, (mm. Hg) Hg) pO..

Experiperament Weight ture No. (Kg.) (~ c.)

(~'g~

Hg)

pH

35.0 39.0 38.8 40.0 38.0 39.O 38.8 39.4 39.2 39.5 39.7

11.8 18.0 11.5 21.0 21.0 24.0 12.0 25.0 23.0 19.5 18.0

498 70.5 66.0 47.1 59.5 50.1 68.8 56.0 50.1 46.9 89.7

7.23 7.24 7.19 7.38 7.14 7.36 7.13 7.32 7.38 7.33 7.12

17.8 12.5 19.0 21.5 28.0 15.5 25.5 23.0 22.5 18.0

65.5 65.0 47.2 60.5 48.4 66.4 57.5 49.3 44.5 86.1

39.5 39.7 39.6 38.5 38.3 39.5 38.2 38.8 39.2

30.5

43.1

7.32

30.0

14.5 20.0 23.5 21.0 12.5 23.0 24.5

63.0 58.4 38.0 41.8 71.2 52.3 47.5

7.11 7.27 7.40 7.32 7.03 7.35 7.28

17.0 19.5 25.0 20.5 13.5 30.0 25.0

1 2 3* 4t 5* 6t 7 8* 9t I0 11" 12t 13" 14+ 15" 16t 17 18 19" 20t 21

4.0 3.0 2.9 4.0 4.0 3.0 3.9 3.9 3.3 4.8 4.3 (died) 4.7 3.8 3.8 3.9 4.0 4.1 3.2 4.5 3.5

(rg~m.

:OH

Femoral artery pO~ pCO, ( ?~Z?IZ. (mm. Hg) ttg)

7.24 7.19 7.37 7.13 7.37 7.13 7.31 7.38 7.35 7.12

40.2 50.1 60.5 47.0 63.0 50.5 64.8 54.7 46.8 45.3 85.9

7,39 7.29 7,17 7,37 7,11 7,36 7.13 7,32 7.40 7.35 7,13

43.2

7.32

26.0

46.0

7.28

60.8 59.6 36.1 42.8 66.5 48.7 47.8

7.12 7.29 7.41 7.32 7.02 7.37 7.29

15.5 21.0 26.0 20.5 14.0 26,5 24.0

59.7 57.7 36.7 40.9 67.5 44.0 48.l

7.12 7.27 7.41 7.32 7.04 7.38 7,30

~First of twins, "~Second of twins.

10 to 75 minutes was monitored. D u r i n g this time, the p u l m o n a r y blood flow was seen to va W considerably despite the constant state of fetal atelectasis. Fig. 1 shows the range of variation in p u l m o n a r y perfusion pressure, p u l m o n a r y flow rate, a n d p u h n o n a r y vascular resistance during these observations. I n 10 experinlents the p u l m o n a r y flow was found to be high and the p u l m o n a r y vascular resistance to be low at tile outset, but as the preparations stabilized the resistances rose from 10 to 80 per cent of their initial values; in 4 preparations the resistances fell from 10 to 75 per cent of their initial levels: a n d in seven the resistance remained constant. I n all preparations a 5 m i n u t e stable state of resistance was achieved before lun~ expansion was studied. I n 9 lambs the femoral artery pressure exceeded the p u l m o n a r y artery pressure during the control period. It would seem, u n d e r these circumstances, that a left-to-right shunt was present through the ductus arteriosus as

pH

6.8 22.0 13.0 20.0 21.0 25.0 15.5 27.0 25.5 20.0 26.0

the result of p u h n o n a r y resistance falling below systemic resistance. These data indicate that variation in fetal p u l m o n a r y vascular resistance is not entirely related to hmg distention. Similar spontaneous changes in the u n e x p a n d e d fetal lamb lung have been reported by Dawes and Mott TM a n d Cassin a n d co-workers 12 in experiments performed by a different method, in which an external flow meter measured the flow through a n anastomosis between the left carotid artery a n d the left p u l m o n a r y artery. T h e observation of this study that stable p u l m o n a r y blood flows a n d resistances were achieved as preparations were left undisturbed suggests that h a n d l i n g the fetus and performing a thoracotomy may be a factor in altering p u l m o n a r y resistance. Ventilation with 5.6 per cent 02, 6.3 per cent CO2, and 88.1 per cent N> In 6 preparations the fetal lungs were initially exp a n d e d a n d ventilated for 15 minutes with a

Volume 67 Number 4

Pulmonary vascular resistance in fetal lambs

571

Mother Pulmonary artery pressure (ram. Hg) Systolic/ Systolic/ diastolic diastolic Mean pressure Mean Femoral artery (ram. Hg)

Left Right atrium lower pres- pulmosure nary ar(ram. tery flow Hg) 9 (c.c./

Femoral artery pressure (ram. Hg)

Pulmonary vas-

cular re- Rectal temsistance (dynes/ perature sec./c?n. -5 • 10') (~ c.)

Femoral artery

40/30 47/35 95/65 75/50 85/55 75/50 80/50 50/25 66/35 100/75 85/40

35 40 75 60 65 60 65 32 50 80 55

70/55 50/35 85/65 60/35 75/40 80/55 75/55 50/40 52/25 65/50 60/35

60 40 75 45 50 70 65 45 37 57 45

1 2 5 3 1 6 4 3 4 1 1

20 20 10 40 11 47 29 10 20 30 25

23.5 15.1 51.9 8.3 35.5 10.8 16.7 33.5 13.1 14.8 14.0

40.0 39.3 38.2 40.0 39.5 38.0 38.8 37.8 37.2 39.5 39.7

99.0 92.5 90.5 104.0 76.0 84.5 119.0 84.0 92.5 90.5 102.0

pCO, (mm. Hg) 34.6 44.0 40.0 35.0 37.8 39.2 36.9 46.0 37.1 32.0 70.0

70/45 65/35 73/45 60/35 68/42 62/38 82/50 80/50 75/50

55 50 55 42 55 50 65 60 58

62/40 55/35 72/47 60/35 60/45 60/40 80/55 77/55 65/45

50 45 55 47 52 50 65 65 55

1 1 1 3 1 1 2 1 I

70 10 9 15 24 10 9 5 19

5.5 74.8 47.9 23.4 16.9 39.1 55.9 I02.2 22.6

39.8 39.8 39.1 :38.8 38.3 39.5 38.2 38.0 38.2

79.0

35.3

7.25

98 0 87.0 106.0 67.5 85.0 71.5 92.5

34.9 39.4 29.6 28.9 33.7 36.1 32.8

7.40 7.28 7.51 7.54 7.50 7.46 7.49

Mean

min.)

gas m i x t u r e similar to the content of gases in the blood as it enters the lungs. T h e gas consisted of 5.6 p e r cent 02, 6.3 p e r cent CO2, a n d 88.1 p e r cent N2. A s u m m a r y of the results of this e x p e r i m e n t is shown in T a b l e I I . This gas mixture did not cause any significant change in the femoral artery blood gases; the m e a n pO2 in the femoral artery before expansion was 21.2 ram. H g a n d after expansion was 19.6 mm. H g with a s t a n d a r d error of the differences of 1.39 a n d p ---- > 0.3; the m e a n pCO2 in the femoral artery before expansion was 54.4 mm. H g a n d after expansion was 56.7 mm. H g with a s t a n d a r d error of the differences of 3.81 a n d p = > 0.5. I n each p r e p a r a tion the p u l m o n a r y resistance was noted to fall concomitantly with a m a r k e d increase in p u l m o n a r y blood flow; there was little change in p u l m o n a r y artery perfusion pressure with the expansion of the lung. Dawes, 7 Cook, s a n d Cassin a n d their coworkers 12 have shown t h a t expansion of fetal

pO, (ram. He)

pH

Systolic/ diastolic Mean

7.43 7.39 7.47 7.47 7.41 7.50 7.45 7.39 7.45 7.52 7.21

115/95 140/110 115/100 100/70 100/70 105/75 115/90 110/80 140/110 110/85 120/85

145/105 120 105/55 80 115/90 I00 80/55 60 150/110 125 80/65 70 125/100 1105 125/100 105 120/100 110

100 125 110 80 80 95 100 90 125 95 100

l a m b lungs with nitrogen results in a fall in p u l m o n a r y vascular resistance, b u t to a lesser degree than with oxygen or air. Cassin 12 has also shown that 7 p e r cent CO2 in N2 causes a lesser d i m i n u t i o n in p u l m o n a r y resistance than N2 alone, a n d that 6.7 to 7.6 p e r cent CO2 in air causes a lesser diminution of p u l m o n a r y resistance t h a n air alone. Thus, expansion of the lungs with a gas, w h e t h e r or not it changes arterial tensions of pCO2 or pO2, results in a fall in p u l m o n a r y vascular resistance, b u t the m a g n i t u d e of the change is influenced by the pO2 a n d pCO2 of the distending gas. T h e effect of expansion of fetal ateleetasis with d e o x y g e n a t e d d e x t r a n , o x y g e n a t e d dextran, o x y g e n a t e d blood, a n d oxygen. I n 3 lambs (Nos. 10, 18, a n d 21), following a control period, the lungs were first e x p a n d e d with 37 ~ C. N2-bubbled 6 per cent dextran in isotonic saline solution, a n d rhythmically flushed by alternate injection a n d w i t h d r a w a l of the same aliquot of fluid. This fluid was

572

Lauer et al.

October 1965 MAXIMUM & MINIMUM OBSERVATION DURING CONTROL

7O

(MINUTES OF OBSERVATION) 75 15 33 36 I0 I$ 3 5 3 5 12 4 5 4 8 3 9 II 1

I

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9

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19 ~ 0

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EXPERIMENT NUMBER

Fig. I. Maximum and minimum observations during control period. The data presented in this diagram show the widest variations observed throughout the entire control period. In all preparations a 5 minute stable pulmonary resistance was required before pulmonary inflation was carried out.

T a b l e II

ExperiFemoral artery ment pO,, pCO~ d No. from. Hg) {mm, Hg) I No ventilation 2 3 6 7 8 9

22.0 13.0 25.0 15.5 27.0 25.5

50.1 60.5 50.5 64.8 54.0 46.8

pH 7.29 7,17 7.36 7.13 7.32 7.40

Pulmonary artery po._ pcoz (ram, Hg) (turn, Hg) l 7.8 11.5 24.0 12.0 25.0 23.0

70.5 66.0 50.1 68.8 56.0 50.1

Le[t atrium pc'o.. [ from. Hg) !

pH

po~ (ram. Hg)

7.24 7.19 7.36 7.13 7.32 7.38

18.0 12.5 28.0 15.5 25.5 23.0

65.5 65.0 48.4 66.4 57.0 49.3

7.24 7.19 7.37 7.13 7.3 l 7.38

21.5 13.5 26.0 21.5 23.6 19.0

51.2 70.1 43.1 60.8 52.0 48,4

7.23 7.09 7.40 7.12 7,31 7.39

pH

Ventilation with 6.3 per cent CO=, 5.6 per cent 0~,, and 88.1 per cent N~ 2 3 6 7 8 9

23.5 12.5 20.5 18.0 24.5 19.0

59.0 77.0 41.4 65.8 48,7 48.8

7.22 7.08 7,43 7.11 7.32 7,39

22.0 11.5 20.5 17.0 25.0 17,5

61.0 79.0 43.2 67.3 51.0 50.5

7.27 7.07 7.38 7.09 7.30 7.38

Volume 67 Number 4

Pulmonary vascular resistance in [etal lambs

removed by tracheal drainage without introduction of air and the lungs were then expanded and flushed with oxygenated 6 per cent dextran in isotonic saline solution at 37 ~ C. The trachea was again drained, and the lungs expanded, and rhythmically flushed with heparinized blood from the maternal femoral artery. The blood was drained from the trachea, and the lungs expanded and ventilated with 100 per cent oxygen. This sequence was selected because the lungs were first expanded mechanically with a hypoxic hypocarbic fluid mixture (nitrogenated dextran), then mechanically expanded with provision of a small amount of oxygen (oxygenated dextran), then mechanically ventilated with the provision of larger amounts of oxygen (maternal femoral artery blood), and finally ventilated with full oxygen stimulation (100 per cent 02). A typical sequence is shown in Fig. 2. Following the initial expansion with deoxygenated dextran in isotonic saline solution, a small rise in blood flow through the right lower pulmonary artery, a fall in pulmonary artery pressure, and a rise in left atrial pressure were noted. Each succeeding ventilation resulted in a small transient rise in pulmonary blood flow with little change in pulmonary artery or left atrial pressure. A large rise in pulmonary blood flow was observed when the lungs were first flushed

Femoral artery pressure (mm. Hg) Systolic/ diastolic Mean

Pulmonary artery pressure (mm. Hg)

573

with oxygenated dextran, but as flushing continued oxygen was extracted from the fluid and pulmonary flow returned to near control levels. Arterial blood produced a response similar to that of oxygenated dextran in saline solution. Expansion and ventilation with 100 per cent oxygen produced the greatest fall in pulmonary resistance of the sequential ventilations. This study suggests that a small fall in pulmonary resistance results from the mechanical expansion of the lungs and that the provision of oxygen in the expanding fluid produces marked diminution in pulmonary resistance. Effect of vagotomy, atropine, and ismeline on pulmonary vascular resistance. In an effort to delineate the controlling mechanism of the fall in pulmonary vascular resistance with the expansion of fetal atelectatic lung, the parasympathetic nerve supply to the lungs was blocked by vagotomy and atropinization and the sympathetic supply was blocked by administration of ismeline. In 3 lambs, the response of pulmonary vascular resistance to ventilation with 10 per cent CO2 and 90 per cent 02 was observed, and then bilateral vagotomy was performed. The results of these experiments are shown in Fig. 3. After stabilization of the preparation following vagotomy, a control period without ventilation was observed, and the lungs were again ventilated with 10 per cent

Le[t atrium

Systolic/ diastolic

Mean

(mean)

Right lower pulmonary artery flow

pressure

(ram. ng)

Pulmonary vascular resistance (dynes/sec./ cm. -5 x 104)

45/35 95/65 75/50 80/50 50/25 66/35

40 75 60 65 32 50

50/35 85/65 80/55 75/55 50/40 52/25

40 75 60 65 45 37

2 5 6 4 3 4

20 10 47 29 10 20

15.1 51.9 10.8 16.7 33.5 13.1

55/35 95/60 65/40 65/45 55/25 80/35

40 75 50 55 30 52

55/35 80/60 65/45 55/35 50/35 95/50

40 70 55 45 40 70

4 6 4 4 4 4

52 57 63 80 126 87

5.5 8.2 6.3 4.0 2.2 5.9

574

Laucr c t a l .

Oct.ber t965

INFLATION

EA, mm/Hg RA. mm/Hg R. L.R A. FLOW CC/MIN. L,A.

mm/Hg

OF

FETAL

LAMB

5O

o /

"

.

.

.

.

/

.

I

I ~ 1 7 ................. 6

]~_

.....

I

o

:r

o ' ,~o

o INFLATIONS

I st 2 nd DEOXYGENATED DEXTRAN P02=18

A

F,A. mm/Hg PA. mm/Hg R.LR A. FLOW cC/MIN. L.A.

I 0 0 ~..~=~\=~_~ 50 [ O

,oo~

"

-

"

~

5th

~

0 I005 0 ~

'

V

( ' ' ' ~ ' - ' ' '. ~. . . . .

O I0

oXYGENATED OEXTRAN P02"520

B

F.A. IO 5

mm/Hg

IO RA. 5 mm/Hg

LUNGS

K

I

I

~

I ~ ~ " " ~ ............ I ........

IO R.L,I~A. FLOW 5 Cc/MIN. L.A. 2I mm/Hg ARTERIAL BLOOD PD 2 =80

r

INFLATIONS

Iiit

Fig. 2. For legend see opposite pa~e.

ARTERIAL BLOOD PO2--3o 5th

I00%

02

I 0 0 % 02 AFTER 5 MIN.

Volume 67 Number 4

Pulmonary vascular resistance in fetal lambs

CO2 and 90 per cent O.o. I n each preparation the initial ventilation resulted in a marked fall in resistance. Following vagotomy and the cessation of ventilation, the resistance again rose to high levels, but fell to low levels in response to a second ventilation with 10 per cent CO2 and 90 per cent 02. In four preparations following observation of the effect of ventilation on the fetal lungs with 100 per cent 02, the ewes and fetal lambs were given intra-arterial atropine (2 rag. per kilogram) and their condition was allowed to stabilize for 15 to 20 minutes. The fetal lungs were again ventilated with 100 per cent 02. In 3 preparations the mother and fetus were then given ismeline intravenously (l mg. per kilogram) to block adrenergic responses and 15 to 20 minutes was allowed for stabilization. The fetal lungs were again ventilated. With each ventilation there was a marked fall in pulmonary vascular resistance, thus indicating that the change in resistance is not mediated through cholinergic or adrenergic nerve supply. The results of these experiments are shown in Fig. 4. DISCUSSION The fall in pulmonary vascular resistance of fetal lambs' lungs has been shown to relate to a decrease in the circulating arterial level of p C 0 2 and to an elevation in the level of pOzS, is However, expansion of fetal lungs

575

with a gas that fails to alter arterial levels of pCOz and pOz is capable of producing a marked fall in pulmonary resistance. Thus, it appears that the vascular resistance change is not entirely dependent on changes in circulating blood gases. Only a small decrease

hi I00

u z ~ 90 co ,,,fl, ~" 80 o~ zo >~ ~ 60 z ~ 50 g" 40 ~ 30 zE ~ ao

/

o

o

\ \ \

Ox \

Gk

o

N0 VENT.

VENTWITH 10% (;02 9 0 % 02

NO VENT.

VENT.WITH 10% CO2 90% 02

Fig. 3. Effect of vagotomy on the response of pulmonary vascular resistance to inflation of the fetal lung.

Fig. 2. Response in the femoral artery (F.A.) pressure, pulmonary artery (P.A.) pressure, right lower pulmonary artery (R.L.P.A.) flow and left atrial (L.A.) pressure in the fetal lamb (No. 18) to expansion of the lungs with deoxygenated dextran in saline solution, oxygenated dextran, arterial blood, and 100 per cent oxygen. Stippled vertical line indicates onset of inflation. A, Expansion with deoxygenated dextran in saline solution, first, second, and fifth inflations. Note the drop in pulmonary artery pressure and increase in pulmonary flow with initial inflation. This transient effect may be the result of the sudden expansion of large vessels with the initial inflation. The succeeding ventilations were associated with a rise in pulmonary artery pressure a n d fall in pulmonary flow to near preinflation levels. B, Expansion with oxygenated dextran in saline (pO2 ~ 520 mm. Hg). Note the immediate small f011 in pulmonary artery pressure and large rise in pulmonary blood flow. Further ventilations with this same aliquot of dextran in saline solution were associated with a return of the pulmonary pressure and flow to near preinflation levels, and the pO2 of the fluid fell to 16 mm. Hg. C, Expansion and ventilation with arterial blood and 100 per cent 02. Note the immediate fall in pulmonary resistance as indicated by the rise in pulmonary blood flow and slight fall in pulmonary pressure with the first inflation with arterial blood. At the fifth inflation, oxygen has been extracted from the ventilating blood and the pulmonary resistance has again risen9 Ventilation with 100 per cent 02 results in a large fall in pulmonary resistance which is maintained after 5 minutes of ventilation.

5 76

October 1965

L a u e r et al.

I00 w

Z cO hi

80

r

>-

60

'5 .J

5O

O. '5

40

M. O ~-

2O

2 W

Fig. 4. Effect of cholinergic and adrenergic blockade on the response of pulmonary vascular resistance to inflation of the fetal lung.

or no change in pulmonary resistance occurs when the fetal lungs are expanded with saline solution 7 or deoxygenated dextran, thus indicating that the mechanical effects of expansion play a lesser part in the Inechanism of this fall in resistance. The addition of oxygen to a fluid used to expand fetal lungs causes a marked fall in puhnonary resistance. These observations suggest that small changes in pCO~ and pO2 environment surrounding the pulmonary arterioles are capable of altering vascular tone without changing circulating arterial pCO,, and pO.,. Cook and associates s have suggested that the anatomic proximity of the pulmonary arterioles to the alveoli places them in a position to respond directly to changes in alveolar gas tensions. The effect on pulmonary resistance of gaseous distention of the fetal lung is not ablated by vagotomy, atropinization, and blockade with ismeline. This indicates that the response is not mediated through cholinergic or adrenergic nerve supply and supports the view that the response is mediated locally.

NO VENT

i00% 02

NO VENT

IOO% 02

NO VEN'E

IOO% 02

SUMMARY

1. Lambs born by cesarean section and still connected to placental circulation were used to study factors controlling pulmonary vascular resistance in the fetus. 2. During a control period before expansion of the fetal lungs, varying from 10 to 75 minutes, marked spontaneous changes in pulmonary blood flow and resistance were observed. 3. Expansion of fetal lungs with a gas that caused no significant change in circulating arterial pO2 or pCO2 resulted in an increase in pulmonary blood flow and marked decrease in pulmonary resistance. 4. Expansion of fetal hmgs with deoxygenated dextran in saline solution produced only a small fall in pulmonary resistance; whereas expansion of fetal lungs with oxygenated dextran or arterial blood resulted in a marked fall in pulmonary resistance. 5. Vagotomy, atropinization, and administration of ismeline did not prevent the fall in pulmonary resistance when the fetal lungs were ventilated.

Volume 67 Number 4

Pulmonary vascular resistance in fetal lambs

REFERENCES

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