response the pulmonary vasculature to hypoxia …...rudolph, dept. of pediatrics, albert einstein...

Journal of Clinical InvestigationVol. 45, No. 3, 1966

Response of the Pulmonary Vasculature to Hypoxia andH+ Ion Concentration Changes *

ABRAHAMM. RUDOLPHt ANDSTANLEYYUAN(From the Department of Pediatrics, Albert Einstein College of Medicine, New York, N. Y.)

Considerable controversy regarding the effectsof hypoxia on the pulmonary vasculature hasarisen over the past few decades. The literaturehas been extensively reviewed by Fishman (1),and it is now generally accepted that hypoxia is apulmonary vasoconstrictor. Much of the con-troversy has centered around the interpretation ofa small elevation of pulmonary arterial pressure inthe face of an increase in cardiac output related tothe hypoxic stimulus. Some investigators calcu-lated a small increase of pulmonary vascular re-sistance, whereas others could not confirm this ob-servation. Most studies were performed in adultanimals, or in adult humans, but more recently at-tention has been directed to hypoxic responses inthe newborn animal, in view of the greater re-sponsiveness of the pulmonary vasculature at thisage.

The relationship between the degree of pulmo-nary vascular response and the level of hypoxiahas received only little attention, and usually aconstrictor response to a single low oxygen gas in-halation has been reported. Recently Thilenius,Hoffer, Fitzgerald, and Perkins (2) attempted torelate pulmonary vascular resistance change to thelevel of inspired gas oxygen tension, but no ob-vious relationship could be demonstrated. Lil-jestrand (3) in 1958 suggested that the pulmonaryvascular response to hypoxia may be related tothe production of local Ho ion concentrationchanges in the lung. More recently Enson and as-

* Submitted for publication June 25, 1965; acceptedDecember 2, 1965.

Supported by U. S. Public Health Service NationalHeart Institute grants HTS5532 and HE08378, and bya grant-in-aid from the Westchester Heart Association.

t This work was accomplished during tenure as aCareer Scientist of the Health Research Council of theCity of New York, under contract 1-210.

Address requests for reprints to Dr. Abraham M.Rudolph, Dept. of Pediatrics, Albert Einstein College ofMedicine, Eastchester Rd. and Morris Park Ave., NewYork, N. Y. 10461.

sociates (4) described a relationship between theresponse to hypoxia and the level of H+ ion con-centration.

The purpose of the present study was 1 ) to at-tempt to delineate the effects of varying degreesof hypoxia induced by breathing low oxygen gasmixtures on the pulmonary vasculature of the new-born calf; 2) to study possible interrelationshipsbetween pulmonary vascular response, hypoxia,and H+ ion concentration; 3) to assess the mecha-nism of the hypoxic response; and 4) to study thegeneral hemodynamic effects of hypoxia in thenewborn animal.

MethodsNaturally born Holstein calves aged 9 to 36 hours

were anesthetized with sodium Pentothal in doses of 15 to20 ml of a 2.5% solution given intravenously. An endo-tracheal tube with an inflatable cuff was inserted perorally,and anesthesia was then maintained with a gas mixturecontaining i to 1% Fluothane and approximately 30%oxygen and 70% nitrous oxide. Spontaneous breathingwas first allowed, while an incision was made throughskin and muscle down to parietal pleura in the fourth leftintercostal space. Positive pressure breathing was thenadministered with a Harvard respiratory pump by usinga tidal volume of 350 to 500 ml and a frequency of 16 to18 per minute. The expiratory tube from the pump wasplaced under 2 to 3 cm of water to slightly elevate endex-piratory pressure and so help to maintain expansion ofthe lungs with the chest open.

The ductus arteriosus was isolated and ligated twicewith heavy suture material. An electromagnetic flow-meter probe was placed around the main pulmonary ar-tery after minimal dissection. A polyvinyl tube withseveral side openings and a sealed tip was placed in theleft atrium and the main pulmonary artery by directpuncture into these structures. Another catheter waspassed through the internal mammary, artery into theaorta. In two animals a multiple side-hole catheter waspassed through a small branch of the middle pulmonaryvein into the main pulmonary vein for sampling and pres-sure recording. The pericardium was closed; the chestwas closed in layers, and the flowmeter connections andcatheters were exteriorized. Air and fluid were carefullyremoved from the pleural cavity. A polyvinyl catheterwas then passed through a hind-leg vein into the inferior

399

ABRAHAMM. RUDOLPHAND STANLEYYUAN

TABLE I

Effects of high and low oxygen concentrations in inspired air on pulmonary arterial pressure, pulmonary blood flow, andpulmonary vascular resistance at varying levels of blood H+ ion concentration*

Pressures Pulmo-Oxygen Pulmo- nary

in Aorta PA LA nary vascu-inhaled blood lar re-

Calf Age Time gas S D M S D M M flow sistance Po0 PCO2 pH

% SmmHg

Calf no. 1 (12 hours)Buffer infusionBuffer infusion

Buffer infusionBuffer infusionLactic acid infusion

Calf no. 2 (10 hours)Buffer infusion

Lactic acid infusion




Buffer infusion

Calf no. 3 (12 hours)Buffer infusion

Buffer infusion




Both vagosympathetictrunks cut

Calf-no. 4 (10 hours)

Lactic acid infusionLactic acid infusionBuffer infusion



Lactic acid infusionBuffer infusion

7:21 50 1807:25 50 1657:37 50 1457:45 50 150

8:02 10 1608:09 10 1378:19 50 1458:26 10 1608:30 10 1058:36 10 1408:46 100 145

5:26 100 905:30 10 955:37 100 1105:47 10 1255:55 100 150

5:57 100 1456:10 100 1556:15 100 1506:21 100 1406:26 100 1426:33 10 1356:34 10 1256:40 100 1456:54 100 1406:59 10 1207:13 100 1357:20 10 1357:25 100 135

5:35 100 885:47 100 75S:52 10 835:56 10 706:06 100 906:21 100 150

6:25 10 1106:27 10 1126:33 100 906:45 100 1206:49 10 1106:54 10 1107:07 100 1107:12 10 1107:17 10 1027:24 100 1007:29 100 807:35 10 68

5:48 100 1406:15 100 1306:23 12 1606:32 12 1706:40 12 1556:59 12 1507:10 100 1257:18 100 1007:23 100 1457:32 12 2007:39 12 1907:50 12 2008:05 100 1408:11 100 1258:20 100 1208:26 12 140

125 153 89 27115 145 88 25110 130 88 27115 130 90 27120 130 100 40105 120 110 45115 129 75 25120 125 90 2755 65 97 3095 115 125 45

110 125 83 28

45 60 68 1560 75 63 2075 95 68 2390 110 100 40

105 125 78 20100 120 80 18105 125 88 20105 125 85 2590 115 90 2090 115 95 2090 115 155 7075 102 150 70

105 125 80 25100 H15 125 55

70 100 150 6055 75 98 2360 80 115 3065 92 100 25

68 80 48 2550 60 45 3060 70 57 3040 50 47 3365 80 50 28

110 125 65 3375 85 98 5582 95 110 6565 72 57 3390 110 60 3085 88 105 7285 90 113 8085 95 87 5085 95 118 7285 88 125 8072 85 72 4260 72 68 4052 60 83 58

110 120 45 18115 125 47 18120 135 59 23145 156 85 48135 130 95 55120 120 53 27110 115 40 22

85 90 50 30125 132 53 25160 175 97 58150 165 95 53150 175 98 55

120 135 50 23100 115 45 18105 112 43 23120 130 67 35

50 850 950. 955 1160 675 440 450 358 885 850 8

40 1140 1343 1363 1247 1345 1348 1150 1150 1155 11

105 10102 12

50 1080 15

105 1060 1465 1162 13

35 935 1140 1135 1139. 1242 1170 882 940 742 782 590 367 7

90 398 355 750 666 5

30 435 435 470 480 540 429 .538 843 775 580 573 538 433 635 548 6

Llmin- mmHg/ mmHgule L/min-

ute3.9 10.8 245 7.194.0 10.2 260 28 7.234.8 8.1 260 26 7.294.4 10.0 250 21 7.253.1 17.5 24 '34 7.212.9 24.5 16 34 7.192.8 12.8 270 37 7.192.9 16.3 14 7.274.8 10.4 11 23 7.343.8 20.3 20 7.193.3 12.7 600 38 7.18

6.6 4.4 434 15 7.426.1 4.4 18 16 7.386.3 4.8 400 21 7.326.6 7.5 18 22 7.336.8 5.0 420 7.365.2 6.2 450 22 7.295.2 7.1 450 7.284.6 8.5 450 25 7.254.6 8.5 540 28 7.254.8 9.2 420 7.224.4 23.0 20 29 7.204.1 22.0 17 23 7.224.6 8.7 415 7.255.2 12.5 450 7.144.2 22.6 18 36 7.169.2 5.0 460 15 7.318.1 6.7 18 15 7.339.2 5.3 450 16 7.32

3.8 6.9 430 20 7.265.7 4.2 530 14 7.405.4 5.3 32 20 7.316.6 3.6 19 15 7.404.8 5.6 560 20 7.324.0 7.8 300 34 7.244.1 14.7 25 37 7.254.1 17.3 21 37 7.244.8 6.7 350 32 7.253.8 9.0 270 46 7.223.0 24.6 24 46 7.192.6 32.2 21 44 7.193.4 17.2 415 50 7.143.2 26.8 35 41 7.182.7 34.5 23 41 7.172.9 16.6 390 39 7.182.6 16.9 420 39 7.201.4 41.8 27 37 7.20

3.4 7.7 590 15 7.323.8 7.6 550 14 7.302.8 10.4 44 14 7.303.5 19.7 42 21 7.223.6 20.9 42 20 7.164.3 8.4 43 12 7.332.8 8.6 410 13 7.302.8 10.7 390 19 7.183.2 11.3 510 19 7.213.0 23.4 45 17 7.253.0 25.5 45 16 7.223.0 22.8 43 16 7.263.0 11.5 500 20 7.193.3 8.2 500 16 7.233.2 9.4 550 16 7.312.7 15.6 35 14 7.30

* Abbreviations: PA - pulmonary artery; LA - left atrium; S - systolic; D = diastolic; M - mean; Pos and Pco2 - oxygen and carbon

dioxide tension.

400

PULMONARYVASCULARRESPONSETO HYPOXIA ANDACIDOSIS

vena cava. An additional vinyl catheter was insertedinto a front-leg vein; succinyl choline chloride in dosesof 1 to 2 mg per minute was -then infused continuouslyinto the catheter in the front leg in five calves. After 3to 4 minutes, anesthesia was stopped and ventilation wasmaintained with room air or 30% oxygen in nitrogen byusing positive pressure administered by the Harvardpump.

Pressures were measured in the pulmonary artery,aorta, and left atrium, and in some cases in a major pul-monary vein, by means of Statham P 23 Db pressuretransducers. Mean pressures were obtained by electri-cal integration. Pulmonary arterial flow was measuredwith a gated sine-wave electromagnetic flowmeter.1 Thevelocity tracing so obtained was integrated electrically torecord stroke volume of the right ventricle. Recordingof each beat was made in some experiments, whereas thetotalized integration was recorded in others. Calibra-tions of the electromagnetic flowmeter and probes invitro showed that the response was linear with flow.The flowmeter was calibrated in vivo from the averageof several indicator dilution curves with injection intothe left ventricle and sampling from the aorta, performedwhile the calf breathed 100% oxygen. Right-to-leftshunt at the time of recording of cardiac output was ex-cluded by injection of indicator into the inferior venacava and sampling in the aorta. Indicator dilutioncurves were performed by using indocyanine green withcontinuous sampling through a Waters X-300 cuvettedensitometer, by means of a Harvard continuous with-drawal pump.

Two groups of experiments were conducted: a) Infour calves, aged 6 to 20 hours, the responses of thevarious hemodynamic parameters were observed whenarterial oxygen tension (Po2) was changed acutely fromhigh levels to very low levels at varying levels of bloodH ion concentration. The inhaled gas mixtures usedwere 100% oxygen and 10% oxygen in nitrogen in threecalves and 12%o oxygen in one calf. The blood pH waschanged by infusion of lactic acid or amine buffer (Tris)into the right atrial catheter. Two types of experi-mental procedures were performed. The effect of lower-ing arterial Po2 was examined after blood pH had beenchanged to varying degrees, and also the effect of chang-ing pH at fixed high and fixed low Po2 was examined(Table I).

b) Various gas mixtures of oxygen in nitrogen wereadministered, with oxygen concentrations varying from8 to 100% (8, 9, 10, 12, 15, 21, 37, 50, and 100%). Aftermeasurement of pressures and pulmonary arterial flowand sampling of blood for Po2, Pco2, and pH from theaorta, and in some cases pulmonary artery and pulmonaryvein, lower percentages of oxygen were administereduntil a steady level of pulmonary arterial pressure wasmaintained for several minutes. After successive de-creases in oxygen concentration, similar studies wereperformed as oxygen was increased.

Blood was analyzed for pH, Pco2, and Po2 within 5

1 Kolin-Kado type, Kado, Los Angeles, Calif.

minutes of collection. Blood pH was measured with aRadiometer capillary electrode, Po2 with a Beckmanelectrode, and Pco2 with a Severinghaus electrode, us-ing a Beckman 160 physiological gas analyzer. The oxy-gen electrode was calibrated throughout the whole rangeof Po2 measurements from 0 to about 700 mmHg byblood samples equilibrated in a tonometer at 370 withgases of measured oxygen concentration in nitrogen. Theresponse of the electrode was linear within the wholerange. In two experiments, a Harris needle oxygen elec-trode was inserted into a carotid artery and continuousPo2, pulmonary arterial pressure, and pulmonary bloodflow were recorded during inhalation of 100% oxygenafter breathing 8% oxygen. All recordings were made ona Grass 8 channel polygraph or an Offner recorder. Pul-monary vascular resistance was expressed in resistanceunits of millimeters Hg per liter per minute and wascalculated from the equation, resistance = PA mean - LAmean pressure/pulmonary flow, where PA= pulmonaryarterial, and LA = left atrial. The pressures are ex-pressed in millimeters Hg, and pulmonary flow is ex-pressed in liters per minute.

Results

The results in the two groups of experimentswill be presented separately.

1) Effect of Ha ion concentration changes dur-ing 100%o oxygen inhalation (Table I, Figure 1).The blood pH was reduced to levels of 7.19 to 7.32in all four calves as a result of the surgical pro-cedure. Administration of amine buffer increasedpH and resulted in an increase in pulmonaryblood flow in all animals. Lactic acid reduced pH

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o Po Above 100mm. Hg* Po2 Below 40mm. Hg

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pHFIG. 1. RESPONSEOF PULMONARYVASCULARRESISTANCE

TO CHANGESIN BLOODPH AT DIFFERENT LEVELS OF OXYGENTENSION. Data from four calves in Table I are plotted.Open circles show observations made when oxygen ten-sion (Po2) in arterial blood was above 100 mmHg, andsolid circles show observations during hypoxia when ar-terial Po, was below 40 mmHg.

401


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and caused a consistent, often marked, fall in pul-monary blood flow in three calves (no. 1, 2, 3) butdid not affect the pulmonary blood flow signifi-cantly in one calf (no. 4).

Resting pulmonary arterial mean pressureswhile the calf was respired with high oxygen mix-tures and pH was near normal levels ranged be-tween 30 and 42 mmHg. WhenpH was loweredthere was a significant increase in pulmonary ar-terial mean pressure to levels of 33 to 80 mmHg.Both left and right atrial mean pressures decreasedsignificantly when pH was lowered, and in onecalf (no. 3) marked reductions of 4 to 5 mmHgwere recorded.

Calculated pulmonary vascular resistance wasincreased by reduction of pH. Moderate increaseswere observed when arterial blood pH droppedbelow 7.3, and a progressive increase was notedas pH dropped further (Figure 1).

Response to hypoxia at variable pH levels. Hy-poxia produced minor but inconsistent small de-creases in pulmonary blood flow when pH levelswere above 7.3 to 7.35. When hypoxia was in-duced in the presence of acidosis, a consistent de-crease in pulmonary blood flow occurred duringinhalation of 10% oxygen.

Pulmonary arterial pressure was dramaticallyincreased by hypoxia when pH was below 7.3,whereas only minor changes were noted when pHwas above 7.3. Left and right atrial pressures didnot change significantly when hypoxia was in-duced at higher pH levels, but further reductionsin mean pressures were noted over and above thealready reduced levels when pH was lowered.

Pulmonary vascular resistances were affectedeither minimally or not at all by changing theoxygen concentration of inspired air when pH wasabove 7.3. However, below this level dramaticincreases of pulmonary vascular resistance oc-curred when hypoxia was induced. The lower thepH, the greater was the response of pulmonaryvascular resistance to hypoxia (Figure 1).

The responses of pulmonary arterial pressure,pulmonary blood flow, and pulmonary vascular re-sistance to changes in inspired air oxygen tensionwere examined at two levels with varying He ionconcentrations. With the calf breathing 50 to100% oxygen, arterial or left atrial Po2 levels of245 to 600 mmHg were accomplished. With 10%oxygen inhalation in three calves, Po2 levels of 11

to 32 were constantly achieved, and in one calfbreathing 12%o oxygen Po2 levels of 35 to 45 wereproduced. Pco2 levels in arterial or left atrialblood varied from 14 to 50 mmHg. The maximalchanges in Pco2 were observed soon after lacticacid or buffer infusion. No relationship could,however, be established between the changes inpulmonary blood flow, pulmonary arterial pres-sure, and pulmonary vascular resistance and varia-tion in Pco2.

2) Responses at different levels of hypoxia (Ta-ble II, Figures 2, 6, 7). The resting pulmonaryarterial mean pressures when the calves were ven-tilated with gas mixtures with an oxygen concen-tration of 21%o or greater ranged from 20 to 36mmHg except in one calf aged 4 days (no. 10),in which resting pressure was 18 mmHg. Res-piration with 15%b oxygen resulted in a mild in-crease of pulmonary arterial mean pressure tolevels of 30 to 44 mmHg. Further reduction ofinspired air oxygen levels resulted in a precipitousincrease of pulmonary arterial pressure, and with8%o oxygen, levels of 45 to 95 mmHg wereachieved (Figure 2). The responses of pulmo-nary arterial pressure were greater in those calvesunder 24 hours of age; in the 4-day-old calf theresponse was least striking, but the same generalpattern of response was noted.

Left atrial pressure.- Left atrial pressure rangedfrom 0 to 6 mmHg (mean) while the calves wereventilated with oxygen or air. Only small changesof 0 to 2 mmHg were noted in left atrial mean

pressure with variations of inhaled oxygen; therewas no specific relationship between the change inleft atrial pressure and the gas inhaled.

too0E 80

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22 20la

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P02 mmHg

FIG. 2. RELATIONSHIP BETWEENPULMONARYARTERIAL

(PA) MEANPRESSUREAND ARTERIAL Po2 IN SIX CALVES

IN TABLE II. Data on different calves are representedby different symbols.

404


Aortic pressure. Aortic mean pressures werebetween 80 and 90 mmHg during air or oxygenbreathing in all except one calf (no. 7) in whicha resting level of 125 mmHg was observed. Asoxygen concentration in inspired air was reduced,no significant changes in aortic pressure were ob-served. Increases or decreases of 5 to 10 mmHgoccurred at random as oxygen concentration waschanged, but no consistent pattern was observed.

Pulmonary blood flow. In previous expen-ments, attempts were made to measure pulmonaryblood flow with indicator-dilution techniques byinjecting indocyanine green into the right or leftatrium or pulmonary artery and sampling from theaorta. It became apparent that this method wasnot valid due to shunting, and it was necessary tomeasure pulmonary flow directly by means of aflowmeter on the main pulmonary artery.

Actual levels of total pulmonary blood flow var-ied considerably but were lower in the youngercalves (under 24 hours). During inhalation of airor oxygen, pulmonary blood flows of 1.35 to 2.09L per minute were observed in the younger calves,and 3.9 to 5.6 L per minute in the older calves(over 24 hours). Reduction of oxygen concen-tration in inspired air resulted in a consistent de-crease of pulmonary blood flow of 10 to 35%o ofthe flow during air or oxygen inhalation. An in-teresting change in the pattern of blood flowthrough the main pulmonary artery was observed.The blood velocity as recorded by the electromag-netic flowmeter showed a smooth rounded contourduring ejection while the animal breathed air,but during low oxygen inhalation the ejection wasmore rapid, and a sharper rise and fall with ahigher peak velocity were observed. In spite ofan increase in peak velocity, the total area underthe velocity curve was decreased, indicating a de-crease in stroke volume (Figure 3).

Indicator dilution curves (Figure 4). Ductalshunting was obviated by surgical ligation of theductus arteriosus. During air or oxygen breath-ing indicator dilution curves with indocyaninegreen injected into the pulmonary artery or leftatrium with sampling from the aorta revealed achange in slope on the descending portion of thecurve with a delayed descent, indicating the pres-ence of a left-to-right shunt. Since no other de-fects were present (the ductus having been li-gated), it was assumed that this shunt was occur-

100 ~\~''N. 'PA PRESS. 50 -

mm g.....

MPAVELOCITY _ i .'' _ X

10% 02

FIG. 3. PULMONARYARTERIAL PRESSURE AND BLOODVELOCITY IN MAIN PULMONARYARTERY (MPA) AS MEAS-UREDBY AN ELECTROMAGNETICFLOWMETERIN CALF NO. 2.Marked increase in peak velocity in main pulmonary ar-tery occurs, but stroke volume, as represented by thearea under the flowmeter curve, is actually reduced.Slow tracing started 5 minutes after initial rapidrecording.

ring at the atrial level through the foramen ovale.Injection of indicator into the left ventricle withsampling in the pulmonary artery showed verylate appearance, whereas injection into the leftatrium with sampling from the pulmonary arteryrevealed the early appearance of a small amountof indicator, confirming that the left-to-right shuntwas at the atrial level. The magnitude. of the left-to-right shunt varied from one animal to the other

EFFECTSOF HYPOXIA ON ATRIAL SHUNTING

INHALED INJECTION LA-SAMPLING AORTAGAS L R SHUNT

AIR

9%°2

INJECTION IVC-SAMPLING AORTA

AIR (

R*L SHUNT

9%02

tDYE INJECTION

FIG. 4. INDICATOR DILUTION CURVESSHOWINGLEFT-TO-RIGHT SHUNTIN UPPERTRACING AND ABSENCEOF RIGHT-TO-LEFT SHUNT (THIRD TRACING) WHENCALF BREATHESROOMAIR. During inhalation of 9% oxygen, left-to-rightshunt disappears and large right-to-left shunt is noted inlower tracing. LA = left atrium; IVC = inferior venacava.

405


and was absent in the 4-day-old calf. When hy-poxia was induced, the atrial left-to-right shuntdisappeared.

Injection of indicator into the inferior vena cavawith sampling in the aorta showed an early appear-ance of indicator with a small preliminary hump,demonstrating the presence of a small right-to-leftshunt, while the animal was ventilated with air oroxygen. This right-to-left shunt was markedlyaccentuated during inhalation of low oxygen gasmixtures and in some animals appeared to accountfor as much as half the systemic blood flow. Itwas presumed that the right-to-left shunt wasthrough the foramen ovale, and this was confirmedin two animals in which sampling from the leftatrium when indicator was injected into the in-ferior vena cava showed the same double humptype of curve.

Blood oxygen tension. Oxygen tensions ofaortic and left atrial blood measured simultane-ously were essentially similar in all the observa-tions made. During inhalation of 100%o oxygen,arterial Po2 levels reached only 325 to 500 mmHg, indicating the presence of some right-to-leftshunt, either intracardiac or possibly intrapul-monary. There was considerable variation in thelevels of arterial Po2 reached during inhalation ofvarious gas mixtures, presumably due to somevariation in the degree of ventilation accomplishedand to variability of right-to-left shunting. Dur-ing ventilation with room air, arterial Po2 levelsranged from 50 to 68 mmHg; with 15%o oxygen,the levels were 36 to 47 mmHg; with 12%o oxy-gen, 32 to 38 mmHg; and with 8%o oxygen, 16 to22 mmHg.

Simultaneous Po2 determinations were made inpulmonary venous and left atrial blood samples inthree calves. During inhalation of high oxygengas mixtures, a large difference in Po2 favoringpulmonary venous blood was noted, whereas whenoxygen in inspired air diminished there was a pro-gressively smaller difference in Po2. When pul-monary venous Po2 was below 35 mmHg, onlyminimal differences were observed (Figure 5).In three calves simultaneous pulmonary arterialand aortic or left atrial blood Po2 measurementswere made. A progressive decrease in pulmonaryarterial Po2 was noted as inspired oxygen concen-tration decreased. When arteriat Po2 was below35 mmHg, the levels of pulmonary arterial Po2

500

400IE 300E

ff 200

oc

Pv P02,",I- I -/

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Iit rI. J2

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FIG. 5. PULMONARYVENOUS(PV) AND SYSTEMIC AR-TERIAL POg DURING INHALATION OF VARIOUS CONCENTRA-TIONS OF OXYGEN(CALF NO. 5). During breathing of lowoxygen mixtures, in spite of large right-to-left shunt,only small differences exist.

were only slightly lower than those in the systemicartery.

Hydrogen ion concentrations were allowed toremain at the levels present after the surgical pro-cedure with no attempt at regulation. In all ani-mals pH was below 7.2, and in one animal it wasas low as 7.0. In each individual animal there was,however, a variation of no more than 0.1 pH unitthroughout the experimental period.

Arterial Pco2 levels were quite variable fromone animal to another, and the levels were largelydependent on the state of ventilation maintained.In spite of this wide range, there was, however,little variation of Pco2 within an individual animal.

Pulmonary vascular resistance and oxygen ten-sion. A very striking relationship has been dem-onstrated between the calculated pulmonary vas-cular resistance and the level of. arterial Po2.When Po2 levels were maintained above 100 mmHg, pulmonary vascular resistance ranged from6.5 to 23.4 mmHg per L per minute. This restinglevel of pulmonary vascular resistance was de-pendent on the age and the blood pH of the ani-mals, being higher in the younger and more aci-dotic animals. As Po2 was lowered to 45 to 50mmHg, there was only a small increase in pul-monary vascular resistance, but with further de-crease of Po2 there was a much more precipitousrise of resistance. In the range of arterial Po2 of15 to 30 mmHg there was an extremely markedincrease in pulmonary vascular resistance responseto small changes of -Po2. Although the restinglevels of pulmonary vascular resistance were vari-able, the patterns of response to Po2 changes werequite comparable (Figure 6).

406

PULMONARYVASCULARRESPONSETO HYPOXIA AND ACIDOSIS

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40

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FIG. 6. RELATIONSHIP BETWEENNARY VASCULAR RESISTANCE AND A:CALVES IN TABLE II. Each calf is Iferent symbol.

In view of the fact that only nr

in pulmonary venous and systemels occurred at low Po2 values, w

aration occurred at higher levelFtern of pulmonary vascular j

shown in Figure 7 would be es.4

plotted 'against pulmonary ve

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FIG. 7. PATTERN OF PULMONARYTO CHANGESOF PH AND P02. In thiincreases of pulmonary vascular resexpressed as a per cent of the level almmHg. The changes in pulmonar]with changes in Po2 have been relat(of pH. This information has been (

pilation of the measurements madestudied.

steep portion of the curve would be displaced mini-mally to the right, and the flat portion would notbe changed. Thus if the response of pulmonaryvasculature is related to a direct local response ofthe vessels to Po2 change, the pattern demonstratedwould be essentially similar.

In two animals bilateral section of the vagosym-pathetic trunks did not alter the pulmonary vascu-lar response to acidosis and hypoxia.

Discussion

Observations on the reactivity of the pulmonarycirculation have most frequently been made in hu-man adults and adult dogs. The pulmonary cir-culation in these species has demonstrated remark-ably little response to most physiologic and phar-macologic influences. Since resting pulmonary

CALCULAE PULMO- arterial pressure is quite low and since only smallRTERIAL P03 IN six changes in pressure occur, it has been difficult torepresented by a dif- separate pulmonary vasomotor effects from simple

physical effects related to changes in cardiac out-.inimal put and pulmonary venous or left atrial pressure.

,limal differences Numerous techniques have been developed to over-tic arterial Po2 lev- come these difficulties in interpretation. Himmel-thereas a wide sep- stein, Harris, Fritts, and Cournand (5), by meanss, the general pat- of bronchospirometry, measured blood flow

resistance. cshangre through each lung and demonstrated a reorienta-sentially simlar if tion of flow in response to hypoxia in one lung.nous Po2. The Rudolph and Scarpelli (6) continuously measured

flow through each lung of the dog by means of elec-tromagnetic flowmeters.

The considerably greater response to the pul-monary circulation in the fetal or neonatal animalhas been repeatedly described. The small pulmo-nary vessels of the fetus have thick muscular walls

pH with relatively small lumina, and the pulmonary7.1 arterial pressure is at systemic arterial levels.7.2 After birth, the vessels rapidly lose this thick mus-7.3 cular medial layer and assume the characteristics7.4 of the adult circulation in 2 to 3 weeks (7, 8).

75 loo This is associated with a rapid decrease of pul-g monary arterial pressure toward adult levels, andVASCULARRESPONSES also a loss of the marked physiologic response ofLs figure, the average the circulation over a similar period (9, 10). Insistance (PVR) are view of this great reactivity of the pulmonary vas-t pH 7.4 and P03 100 culature during the fetal and immediate postnataly vascular resistance periods, an excellent experimental model for theed at different levels

leriedroma crn-study of pulmonary vascular response is provided;derived from a com-hsclfcossc scagsi etara rsin all the animals physical factors such as changes in left atrial pres-

sure and blood flow exert relatively small changes

407


compared with those produced by pulmonary vaso-motion. An increase in viscosity could produce anincrease in pulmonary vascular resistance as cal-culated from arterial pressure, as demonstrated inthe Posseuille equation. There was, however, nosignificant increase in hematocrit during hypoxia,and the likelihood of hypoxemia producing an in-creased viscosity by other means is small. Green-berg, Kass, and Castle (11) have shown that littlechange in blood viscosity occurs when normal he-moglobin is reduced.

Although pulmonary vasoconstriction in re-sponse to inhalation of hypoxic gas mixtures hasbeen unquestionably demonstrated in the adult, thechanges in the fetal and neonatal animal are farmore striking. Cook and associates (12) and Cas-sin and associates (13) have stressed the im-portance of a low Po2 in maintaining pulmonaryvasoconstriction in the fetus, and the immediate in-crease of pulmonary blood flow associated withventilation of the lungs with gas containing oxy-gen. James and Rowe (14) demonstrated themarked increase in pulmonary arterial pressureresulting from administration of low oxygen mix-tures to the neonatal human infant. Reeves andLeathers (15) have carefully delineated the nor-mal changes in pulmonary arterial pressure andpulmonary vascular resistance with advancing agein the calf; the marked vascular response to hy-poxia noted in the postnatal period rapidly de-creased as resting pulmonary arterial pressure fell.

Although the greater reactivity of the pulmo-nary circulation in the newborn animal affords anexcellent model to study the responses of the pul-monary vasculature, certain special aspects of theneonatal circulation have to be taken into account.Fetal shunting mechanisms may still be operative,thus making the measurement of pulmonary bloodflow by either Fick or indicator dilution tech-niques most unreliable. During the first 24 hoursafter birth the ductus arteriosus may still be func-tionally patent, thus allowing left-to,-right or right-to-left shunting, depending on the relationship be-tween systemic and pulmonary vascular resist-ances. The absence of any ductal shunt duringinhalation of room air does not preclude the pos-sibility that the ductus may reopen with hypoxemia(16), thus introducing difficulties of interpretationof indicator curves and oxygen saturation data.The foramen ovate also does not provide a com-

plete and competent separation of the left andright atria after birth. A small left-to-right shuntcan be demonstrated very frequently both in thecalf (Figure 4) and in the human infant. Whenpulmonary vascular resistance is elevated, as whenright ventricular outflow obstruction occurs, amarked right-to-left shunt may occur through theforamen ovale. These considerations have beenneglected in many studies relating to measurementof pulmonary vascular resistance and to shuntingmechanisms in the newborn infant and experi-mental animals (15-18).

The difficulties in measurement of pulmonaryblood flow and pulmonary vascular resistance im-posed by these mechanisms were overcome in ourpreparation. Ligation of the ductus arteriosusprevented any shunting into or away from the pul-monary artery, thus assuring the accuracy of theelectromagnetic flow probe around the main pul-monary artery in measuring pulmonary blood flow.Shunting through the foramen ovale also did notinterfere with the measurement of pulmonaryblood flow by the method applied.

The increase in pulmonary vascular resistancewith acidosis at normal or high levels of arterialPo2 confirms the observations of a number ofprevious studies. In our studies no attempt wasmade to distinguish between the effects of increaseof Pco2 or decrease of pH by fixed acid infusion.Bergofsky, Lehr, and Fishman (19) have shownthat the pulmonary vascular response is related toa change of hydrogen ion concentration and that asimilar response occurs either with respiratory ormetabolic- acidosis. These previous studies didnot, however, establish any specific relationshipbetween the level of pH and the pulmonary vas-cular response. Our observations indicate thatpulmonary vasoconstriction occurs when pH fallsbelow 7.30 to 7.35. As pH drops further, a largeincrease in pulmonary vascular resistance is ob-served below levels of 7.15 to 7.2. There thus ap-pears to be a curvilinear relationship between pHand pulmonary vascular resistance.

Although many observations of a pulmonaryvasoconstrictor response to hypoxia have been re-ported, little information is available regarding therelationship between the degree of hypoxia andthe magnitude of the pulmonary vascular response.Several attempts to compare the pulmonary vascu-lar resistance with the level of arterial oxygen

408


saturation have not shown any consistent relation-ship (2, 20, 21). A rise of pulmonary vascularresistance has usually been observed in patientswith chronic pulmonary disease when arterialoxygen saturation falls to 80 to 85% representingaPo2of46to50mmHg (1).

However, Reeves and Leathers (15) haveshown a progressive increase in pulmonary arterialpressure with decreasing concentration in inhaledgases in unanesthetized newborn calves, and Cas-sin and co-workers (13) established a linear re-lationship between the conductance of the pulmo-nary circulation and the Po2 of blood perfusingthe lung. These latter studies were performed inthe fetal lamb and show very wide scatter.

The results of our studies in calves have demon-strated a very definite pattern of pulmonary vas-cular response to hypoxia. Pulmonary arterialpressure and pulmonary vascular resistance showedonly a slight increase as systemic arterial Po2dropped to 50 to 60 mmHg. More significantincreases occurred when Po2 fell to 40 to 45 mmHg, and below this level there was a very steeprise of pulmonary arterial pressure and pulmonaryvascular resistance, indicating an exquisite sensi-tivity of the pulmonary vessels to Po2 changes inthe range below 35 to 40 mmHg. It was not pos-sible to maintain Po2 levels of 18 to 20 mmHg atlow levels of pH for more than a few minutes be-cause of the effect on the myocardium with result-ing circulatory depression (22). However, it ap-peared that the pulmonary vascular response wasmaximal at Po2 levels of 18 to 20 mmHg, and nofurther increase occurred below this level.

The possibility that pulmonary arterial Po2 de-termines the response of the pulmonary vesselshas been considered. Our studies did not sepa-rate the relative roles of pulmonary venous andpulmonary arterial Po2 in pulmonary vascular re-sponse, since pulmonary arterial Po2 also de-creased when oxygen concentration in inhaled airwas reduced.

Enson and associates (4) reported a definite re-lationship between pulmonary vascular resistanceand the levels of Po2 and pH in a group of pa-tients with chronic pulmonary disease. Therewas, however, wide scatter of the data and onlylittle information relating to repeated studies inthe same individual. The interrelationship be-tween pulmonary arterial pressure and pulmonary

vascular resistance and Po2 and pH has been strik-ingly demonstrated in our studies. The mecha-nism of the enhanced pulmonary vasoconstrictorresponse to hypoxia in the presence of acidosis hasnot been elucidated.

Although it is possible that the presence of aci-dosis may result in an increased sensitivity of thevascular smooth muscle to hypoxia, the increasedresponse of vascular resistance to hypoxia couldbe explained on a simple physical basis. The cal-culated pulmonary vascular resistance is an ex-pression of total cross-sectional area of the pul-monary vascular bed; a given decrease in circum-ference or diameter produced by smooth muscularconstriction will result in a relatively small de-crease in cross-sectional area. However, if thesame degree of smooth muscular constriction pro-duces a similar reduction in diameter of the vesselalready partly constricted from some other influ-ence, this same reduction will cause a much greaterdecrease in cross-sectional area and thus a markedincrease in pulmonary vascular resistance.

That a simple physical phenomenon is probablynot the only mechanism involved is suggested bythe fact that marked reduction in Po2 to levelsbelow 25 mmHg could be produced in some in-stances and yet, when pH was normal, no in-crease in pulmonary vascular resistance occurred

On the basis of our studies, the relationship be-tween pulmonary vascular resistance, Po2, and HEion concentration may be represented diagram-matically as depicted in Figure 7. This extremeresponse of the pulmonary vasculature to smallchanges of Po2 in the range 15 to 30 mmHg at de-creased pH may have an important role in thefetal circulation. Blood perfusing the lungs inthe fetus has a Po2 in this range, and this couldprovide a sensitive mechanism for distribution ofblood flow in the fetus. An increase in pulmonaryvascular resistance would divert blood away fromthe lungs and through the ductus arteriosus intothe descending aorta and thus to the placenta.This mechanism could thereby result in an in-crease in blood flow to the placenta where gas ex-change occurs, providing a means of adapting tostress situations interfering with oxygenation ofthe fetus.

In the neonatal period, the development of aci-dosis and hypoxia from any cause may producepulmonary vasoconstriction, which may have sen-

409


ous consequences. An increase in pulmonary vas-cular resistance in the immediate neonatal periodwould -reestablish a fetal pattern of circulation withright-to-left shunting through the ductus arterio-sus and foramen ovale. Pulmonary blood flowwould, be reduced, and whereas this is of no con-sequence in the fetus where oxygenation is car-ried out in the placenta, it would result in a viciouscycle of events in the newborn animal or infant.Acidosis and hypoxia would increase pulmonaryvascular resistance and decrease pulmonary bloodflow, thus further reducing oxygenation and inter-fering with the respiratory compensating mecha-nism to correct acidosis by CO2elimination. This,combined with right-to-left shunting, would pro-duce greater hypoxia and combined metabolic andrespiratory acidosis, with more severe pulmonaryvasoconstriction.

This sequence of events may be important inthe respiratory distress syndrome of the newborninfant (hyaline membrane disease). Suggestiveevidence for a decreased pulmonary blood flow hasbeen presented by Chu and co-workers (23).

The pulmonary vasoconstrictor response to aci-dosis and hypoxia may also be important in thepostoperative period in infancy, particularly afterthoracic procedures. Acidosis develops quitereadily in infants, and if ventilation is decreasedand hypoxia superimposed, pulmonary vasocon-striction may result. In the absence of shuntingmechanisms, total cardiac output may be decreasedif the right ventricle is not capable of maintainingan adequate output. If the foramen ovale is stillpatent, right-to-left shunting could result.

The necessity of the presence of acidosis for asignificant hypoxic vasoconstrictor response pro-vides a relatively simple means of avoiding thismechanism. Rapid correction of acidosis by meansof bicarbonate or amine buffer infusion can rapidlyreverse the general hemodynamic effects resultingfrom pulmonary vasoconstriction.

This mechanism of pulmonary vascular responseto hypoxia and acidosis was not conclusively es-tablished in this study. However, the fact thatvagosympathectomy did not in any way alter theresponse in two animals studied suggests that it isnot mediated through a central reflex pathway andthat it is most likely a local reaction of the vessels.This is supported by Bergofsky and Weinberg

(24), who have shown that strips of pulmonaryartery suspended- in vitro constrict on exposureto hypoxia.

Summary

The pulmonary vascular responses to variationsin blood oxygen tension and He ion concentrationlevels have been studied in the newborn calf. Thedifficulties in measuring pulmonary blood flow inthe newborn animal are discussed. In this study,flow was measured directly with an electromag-netic flowmeter.

When arterial oxygen tension (Po2) is 100 mmHg or above, reduction of pH below 7.30 resultsin a small increase in pulmonary vascular resist-ance. A progressive and more dramatic increasein vascular resistance occurs as pH drops to lowerlevels.

At normal levels of blood pH (above 7.35) re-duction of arterial Po2 produced by inhalation oflow oxygen gas mixtures resulted in minimal in-creases in pulmonary vascular resistance evenwhen arterial Po2 fell to 18 to 20 mmHg. WhenpH was lowered, reduction of Po2 produced an in-crease of pulmonary vascular resistance which wasof significant degree when Po2 fell below about 50mmHg. Further reductions of Po2 resulted invery marked increases in pulmonary vascular re-sistance. A curvilinear relationship between pul-monary vascular resistance and Po2 was estab-lished, with extreme sensitivity of pulmonary vas-cular resistance to Po2 changes in the range 18 to20 mmHg. Also, the lower the pH, the greaterwas the pulmonary vascular resistance responseto Po2 reduction.

The importance of this relationship on shuntingmechanisms through the ductus arteriosus andforamen ovale in the neonatal period is discussed,with particular reference to the respiratory distresssyndrome and to postoperative complications ofthoracotomy in infancy.

References

1. Fishman, A. P. Respiratory gases in the regulationof the pulmonary circulation. Physiol. Rev. 1961,41, 214.

2. Thilenius, 0. G., P. B. Hoffer, R. S. Fitzgerald,and J. F. Perkins, Jr. Response of pulmonarycirculation of resting, unanesthetized dogs to acutehypoxia. Amer. J. Physiol. 1964, 206, 867.

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3. Liljestrand, G. Chemical control of the distributionof the pulmonary blood flow. Acta physiol. scand.1958, 44, 216.

4. Enson, Y., C. Giuntini, M. L. Lewis, T. Q. Morris,M. I. Ferrer, and R. M. Harvey. The influenceof hydrogen ion concentration and hypoxia on thepulmonary circulation. J. clin. Invest. 1964, 43,1146.

5. Himmelstein, A., P. Harris, H. W. Fritts, Jr., andA. Cournand. Effect of severe unilateral hypoxiaon the partition of pulmonary blood flow in man.J. thorac. Surg. 1958, 36, 369.

6. Rudolph, A. M., and E. M. Scarpelli. Drug actionon pulmonary circulation of unanesthetized dogs.Amer. J. Physiol. 1964, 206, 1201.

7. Naeye, R. L. Arterial changes during the perinatalperiod. Arch. Path. 1961, 71, 121.

8. Wagenvoort, C. A., H. N. Neufeld, and J. E. Ed-wards. The structure of the pulmonary arterialtree in fetal and early postnatal life. Lab. Invest.1961, 10, 751.

9. Rudolph, A. M., P. A. M. Auld, R. J. Golinko, andM. H. Paul. Pulmonary vascular adjustments inthe neonatal period. Pediatrics 1961, 28, 28.

10. Emmanouilides, G. C., A. J. Moss, E. R. Duffie, Jr.,and F. H. Adams. Pulmonary arterial pressurechanges in human newborn infants from birth to3 days of age. J. Pediat. 1964, 65, $27.

11. Greenberg, M. S., E. H. Kass, and W. B. Castle.Studies on the destruction of red blood cells.XII. Factors influencing the role of S hemoglobinin the pathologic physiology of sickle cell anemiaand related disorders. J. clin. Invest 1957, 36, 833.

12. Cook, C. D., P. A. Drinker, H. L Jacobson, H.Levison, and L. B. Strang. Control of pulmonaryblood flow in the foetal and newly born lamb. J.Physiol. (Lond.) 1963, 169, 10.

13. Cassin, S., G. S. Dawes, J. C. Mott, B. B. Ross, andL. B. Strang. The vascular resistance of thefoetal and newly ventilated lung of the lamb. J.Physiol. (Lond.) 1964, 171, 61.

14. James, L. S., and R. D. Rowe. The pattern of re-sponse of pulmonary and systemic arterial pres-

sures in newborn and older infants to short periodsof hypoxia. J. Pediat. 1957, 51, 5.

15. Reeves, J. T., and J. E. Leathers. Circulatorychanges following birth of the calf and the effectof hypoxia. Circulat. Res. 1964, 15, 343.

16. Moss, A. J., G. Emmanouilides, and E. R. Duffie, Jr.Closure of the ductus arteriosus in the newborninfant. Pediatrics 1963, 32, 25.

17. Rudolph, A. M., J. E. Drorbaugh, P. A. M. Auld,A. J. Rudolph, A. S. Nadas, C. A. Smith, andJ. P. Hubbell. Studies on the circulation in theneonatal period. The circulation in the respira-tory distress syndrome. Pediatrics 1961, 27, 551.

18. Nelson, N. M., L. S. Prod'hom, R. B. Cherry, P. J.Lipsitz, and C. A. Smith. Pulmonary function inthe newborn infant. II. Perfusion-estimation byanalysis of the arterial-alveolar carbon dioxidedifference. Pediatrics 1962, 30, 975.

19. Bergofsky, E. H., D. E. Lehr, and A. P. Fishman.The effect of changes in hydrogen ion concentra-tion on the pulmonary circulation. J. clin. Invest.1962, 41, 1492.

20. Cournand, A. Some aspects of the pulmonary circu-lation in normal man and in chronic cardiopul-monary diseases. Circulation 1950, 2, 641.

21. Fishman, A. P., J. McClement, A. Himmelstein, andA. Cournand. Effects of acute anoxia on thecirculation and respiration in patients with chronic-pulmonary disease studied during the "steadystate." J. clin. Invest. 1952, 31, 770.

22. Talner, N. S., S. E. Downing, and T. H. Gardner.Influence of hypoxemia and acidemia on left ven-tricular function. Proceedings of the Society forPediatric Research, 35th Annual Meeting, Phila-delphia, May 1965.

23. Chu, J., J. A. Clements, E. Cotton, M. H. Klaus,A. Y. Sweet, M. A. Thomas, and W. H. Tooley.The pulmonary hypoperfusion syndrome. Pedi-atrics 1965, 3S, 733.

24. Bergofsky, E. H., and M. Weinberg. Cellular mecha-nism for pulmonary pressor response to hypoxia.Fed. Proc. 1965, 24, 645.

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response the pulmonary vasculature to hypoxia …...rudolph, dept. of pediatrics, albert einstein...

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