J. Physiol. (1987), 383, pp. 413-424 413With 3 text-figures

Printed in Great Britain

IN UTERO VENTILATION WITH OXYGEN AUGMENTS LEFTVENTRICULAR STROKE VOLUME IN LAMBS

BY MARK J. MORTON, C. WRIGHT PINSON AND KENT L. THORNBURG*From the Departments of Internal Medicine (Cardiology, Heart ResearchLaboratory), Surgery and Physiology, Oregon Health Sciences University,

Portland, OR 97201, U.S.A.

(Received 26 November 1985)

SUMMARY

1. In order to determine mechanisms for increased stroke volume at birth, leftventricular function was investigated in eight fetal lambs during in utero pulmonaryventilation. At surgery fetuses were prepared with a tracheal tube, aortic electro-magnetic flow sensor, and carotid, jugular, pericardial and left atrial catheters.

2. After 8-3+1-5 (mean+S.D.) post-surgery days and at 137+3 days gestation,haemodynamic values were obtained before and during pulmonary ventilation inutero.

3. During ventilation, 02 content increased from 7'3+ 2-1 to 14-7 + 2-7 ml dl-1(P <0O001), right atrial pressure from 3-0+ 1-3 to 4-5+ 1-6 mmHg (P < 0-05), leftatrial pressure from 2-5 + 1-2 to 10-2 + 3 7 mmHg (P < 0-001), left ventricular strokevolume from 1 1 +0 4 to 1 9+ 1-2 ml kg-' (P < 0 05), and heart rate from 160+ 21 to183+ 11 beats min' (P < 005).

4. During 02 ventilation, left ventricular function curves relating stroke volumeto left atrial pressure were shifted upward.

5i. 02 ventilation produced rapid, reversible increases in left ventricular strokevolume which approximate increases in stroke volume at birth.

INTRODUCTION

After birth, as the pulmonary and systemic circuits are perfused serially and theplacental circuit is lost, the right ventricle ejects against a pressure which is lowerthan normal fetal arterial pressure and the left ventricle against an increased arterialpressure (Rudolph & Heymann, 1974). During this transition period, both ventriclesincrease their outputs above their respective fetal levels to meet the demands ofaugmented 02 consumption inherent in the new-born condition (Klopfenstein &Rudolph, 1978; Lister, Walter, Versmold, Dallman & Rudolph, 1979; Rudolph,1985). One can estimate from published data (Klopfenstein & Rudolph, 1978; Listeret al. 1979; Anderson, Bissonnette, Faber & Thornburg, 1981) that right ventricularstroke volume increases from 1-5 to 2-0 ml kg-' and left ventricular stroke volumefrom 1 1 to 2-0 ml kg-' at birth.

* To whom correspondence should be addressed at the Department of Physiology, L334, OregonHealth Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201, U.S.A.

M. J. MORTON AND OTHERS

How the natal left ventricle can increase its output nearly twofold in the face ofincreased after-load is unknown since it has been shown that (1) output remainselevated after the 8-adrenergic inotropic effects of circulating catecholamines areantagonized (Klopfenstein & Rudolph, 1978), and that (2) left ventricular outputcannot be increased significantly by increasing mean left atrial pressures in the fetus(Thornburg & Morton, 1986). Nevertheless, Anderson, Manring, Glick & Crenshaw(1982) have suggested that both increased end-diastolic dimension and increasedcontractility augment left ventricular stroke volume at birth. Since improved leftventricular performance is temporally associated with pulmonary ventilation atbirth, we investigated whether pulmonary respiration in utero would mimic theincreased left ventricular performance at birth in the absence ofother birth processes.

METHODS

Animals and surgical proceduresTime-bred pregnant sheep (Ovis aries) of various breeds and their fetuses were instrumented at

121-132 days gestation. Sterile surgery was performed according to previously published protocols(Anderson et al. 1981; Thornburg & Morton, 1983; Thornburg & Morton, 1986). Briefly, anaesthesiafor ewe and fetus was induced with methohexital sodium and maintained with 1-5% halothane in50% 02 with a balance of N20. With the ewe in supine position, a mid-line celiotomy was followedby hysterotomy. The fetal head and thorax were exposed. Two 1P7 mm o.d. polyvinyl catheters(Bolab V-8) were advanced to the junction of the superior vena cava and right atrium, via the rightjugular vein. One 1P7 mm o.d. and one 1-3 mm o.d. (Bolab V-5) catheter were advanced to nearthe junction of the brachiocephalic artery and the aorta via the right carotid artery. Adouble-lumen, 5-7 mm polyvinyl tube (Argyle Salem Sump) was advanced to just above the carinavia a tracheostomy.The heart and great vessels were exposed through a left third interspace thoractomy and

pericardiotomy. The ascending aorta was equipped with a cuff-type electromagnetic flow sensor(In Vivo Metric Systems or C and C Instruments) of appropriate internal diameter. A V-5 catheterwas introduced into the left atrial appendage. A Silastic catheter of similar calibre with multipleside-holes in the distal 3 cm was placed in the anterior pericardium with the tip at the cardiac apex.The pericardial incision was left open and the chest was closed in anatomic layers. A catheter

was attached to the fetal skin for communication with the amniotic fluid. All catheters exited theewe's abdominal cavity through stab incisions and were tunnelled to bilateral exit sites on the ewe'sdorsal flanks, where they were placed in pouches. The tracheal and amniotic catheters were joinedin a closed loop to allow for fetal pulmonary drainage. Penicillin (106 u.) was introduced into theamniotic cavity at the end of the procedure.

Laboratory proceduresOn the day of the experiment, the ewe was put into a stanchion and given food and water.

Hydrostatic pressures were converted to electrical signals by I. D. Statham Gould pressuretransducers. Pressures, measured through catheters near or in the right atrium, aortic arch, carinaof the trachea, left atrium, pericardium, and amnion were recorded on a Beckman R612 Dynographrecorder. Transducers were calibrated to the nearest 05 mmHg with a water manometer. Allvascular pressures were referenced to pericardial pressure. The flow sensors were calibratedpre-operatively in vitro using appropriate calibre sheep arteries and blood. The flow meter was setto zero during diastole when aortic flow was assumed to be zero. Left ventricular output (minuscoronary flow) and heart rate were recorded on the strip chart recorder from the flow signal.The outputs from all Dynograph channels were recorded onto floppy disks via a Hewlett-Packard

3437A System voltmeter and 9826 computer. Digital signals were sampled every 10 ms andaveraged every 5 s. All output data from the disk were checked against original strip chart records.

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02 VENTILATION AND FETAL L. V. STROKE VOLUME

°2 or N2

To fetus in utero

Va Ive

Inspiratory phase 1

P.EE.EP.

Expiratory phase

I.a.

Descendingaorta

ID

-

*4" ,, k--

tt "'' ~~I7/

Fig. 1. Diagrammatic arrangement of fetal lamb prepared for chronic in utero ventilation.Catheters were placed in the pericardium, the right atrium (r.a.) via the superior vena cava

(s.v.c.), the brachiocephalic artery via the carotid artery (c.a.) and the left atrium (l.a.).An electromagnetic flow (e.m.f.) sensor was placed on the ascending aorta. The rightventricle (r.v.), left ventricle (l.v.), pulmonary artery (p.a.), and aorta are indicated.Fetuses were ventilated with 02 or N2 (upper right) by a piston pump. During theinspiration phase, gas was forced through the small lumen of a double-lumen tube in thefetal trachea. During the expiration phase, pulmonary gas was expelled through the largerlumen under the recoil of the fetal chest through a water column, which maintained a

positive end-expiratory pressure (P.E.E.P.) of a few cmH20 above amniotic fluid pressure.

Experimental protocolControl values of vascular pressures, left ventricular output and heart rate were recorded. Arterial

blood gas tensions were measured. Fetuses were given the cholinergic blocking agent atropine(0-5 mg kg-') and the 3-adrenergic blocking agent propranolol (1 mg kg-1), to minimize the effectsof autonomic compensatory mechanisms. A second set of 'blocked' haemodynamic values were thenrecorded. These data are referred to hereafter as 'control' data.

In each blocked fetus, left ventricular performance was studied by generating a function curve

relating left ventricular output, measured by the electromagnetic flow sensor, to mean left atrial

.0

415

ft,

M. J. MORTON AND OTHERS

transmural pressure. Function curves were formed by rapidly withdrawing and re-infusing fetalblood through a V-8 catheter as previously described (Thornburg & Morton, 1983, 1986). Briefly,blood was withdrawn into sterile heparinized syringes until left ventricular output was decreasedto one-third of the control value or until mean left atrial pressure was reduced to less than 1 mmHg;the blood was then rapidly re-infused. Additional Ringer solution was infused until a minimumfilling pressure of 8 mmHg was achieved. The procedure usually took 3-5 min.

Following this control function curve, the tracheal tube was connected to a respiration pump(Harvard Apparatus Co., model 607) and the fetus ventilated with 02 as previously described(Willis, Anderson, Thornburg & Faber, 1985). Fig. 1 shows the arrangement diagrammatically. Netinspiratory tracheal pressures were maintained below 20 mmHg, respiratory rate was 40-60 breathsmin-' and tidal volumes were near 15-25 ml kg-' during ventilation. After an approximately 10 minventilation period, left ventricular performance data were collected as described above whileblockade was maintained by administration of supplementary doses of blocking drugs. During thistime arterial blood gas tensions and 02 content were measured. These data are referred to hereafteras '02 ventilation' data.

Ventilation was then discontinued for about 30 min to allow the fetus to reach a new un-ventilatedsteady state before the next procedure. Four fetuses were also ventilated with 6 % CO2 in N2. Datafrom these animals are referred to as 'N2 ventilation' data. N2 ventilation followed 02 ventilationin three fetuses and preceded 02 ventilation in one fetus. Several fetuses were ventilated with 02repeatedly; however, only the first ventilation period was included in the data reported. Allexperimental sessions were concluded by recording haemodynamic data approximately 30 min aftercessation of ventilation experiments. These final data are referred to as 'recovery' data.At autopsy, all fetuses were weighed and dissected to determine fit of the flow sensor, position

of catheters, extent of healing and appearance of the lungs.

Statistical analysisAnalysis of variance was used to test for differences of the haemodynamic variables among

groups, and when present, Tukey's method was used to test for significance between group means

(Wallenstein, Zucher & Fleiss, 1980). Function curve data were subjected to linear regressionanalysis with the ascending and plateau limbs and their intersections determined mathematicallyas previously described (Thornburg & Morton, 1986). Since paired data were available for thecontrol and during 02 ventilation, a paired t test was used to detect differences in the two conditions.The slopes and y-adjusted means of the two limbs of the function curves were compared among

groups by analysis of covariance. The relation between left and right atrial pressures in the controlversus 02 ventilation groups were also compared by analysis of covariance (Snedecor & Cochran,1980).

RESULTS

Eight fetal sheep which were successfully ventilated with 02 in utero after8-3 + 1-5(mean

+

S.D.) post-operative days were included in the study. Four of these were alsoventilated with N2. Their average gestational age was 137+ 3 days and weight,3.9 + 0 7 kg, at the time of experiment. Haemodynamic data were collected before theadministration of blocking drugs to establish the well-being of the fetus. Under theseconditions right atrial pressure was 2-9 + 1-2 mmHg; left atrial pressure,

330 + O-8 mmHg; arterial pressure4555 + 63 mmHg; left ventricular output (minuscoronary flow) 169 + 64 ml min-' kg-'; heart rate 147 +18 beats min-'; haematocrit39*1+5O %.The 'control' and '02 ventilation' data in Table 1 are paired data and were

collected just before blood was withdrawn for the generation of their respectivefunction curves; fl-adrenergic and cholinergic blockade was present. Control datawere not different from data collected before blocking drugs were administered.Several clear haemodynamic changes were found when the fetal lung was ventilated

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02 VENTILATION AND FETAL L. V. STROKE VOLUME

TABLE 1. Haemodynamic values in animals with pharmacologic blockage of cholinergic andfl-adrenergic receptors

Control8

Level of02 significance

ventilation (two-tailed test)8

pH 7-36+0101 7 39+004 n.s.

Pco2 (mmHg) 48-7 +40 42-2 + 4-2 P < 0 01*Po, (mmHg) 18-0+1-7 111-0+ 11810 0-1 > P > 0-05tO2 content (ml dl-P) 7-3+2-1 14-7+2-7 P < 0 001tR.A.P. (mmHg) 30+ 1-3 4-5+ 1-6 P < 0 05L.A.P. (mmHg) 2.5+1-2 10-2+3-7 P < 01001tC.A.P. (mmHg) 5010+880 58-0+1010 n.s.l.v. output (ml min-' kg-l) 166-0 +60-0 356-0 +221-0 P < 0105s.v. (mlkg-') 1.1+0-4 1.9+1-2 P<005H.R. (beats min-') 16010+21-0 183-0+ 1110 P < 0 05

Values are means+S.D. * P < 0105 with one-tailed test. t n = 7. n.s. = not significant.PO2 = partial pressure of 02 in the carotid artery; Pco2 = partial pressure of CO2 in the carotid

artery; R.A.P. = mean right atrial pressure; L.A.P. = mean left atrial pressure; C.A.P. = carotidartery pressure; l.v. = left ventricular; s.v. = stroke volume; H.R. = heart rate.

TABLE 2. Haemodynamic values in animals with pharmacologic blockage of cholinergic and,8-adrenergic receptors

RecoveryN2 from 02

Control ventilation ventilation Level of significance

pH

Pco, (mmHg)Po2 (mmHg)

02 content (ml dl-1)

R.A.P. (mmHg)L.A.P. (mmHg)C.A.P. (mmHg)l.v. output (ml min-' kg-1)l.v.s.v. (ml kg-')H.R. (beats min-')

Values are means + S.D.ations as in Table 1.

8 47-36+0101 7.33+0*02

48-7 +410 47-8+33018-0+1-7 14-3+1-0

7-3+2-1* 4-8+0-6

3-0+ 1.3*2-5+ 1250+8*166+601.1+0-4160+ 21

3-6+0*23-9+ 1356+10209+ 16711 +0-8178+8

57-29+0103 P<0-01,

control > N2> recov(

51-9+3-5 n.s.13-9+1P7 P<0-01,

control > N2> recov

4.6+1.1* P<0105,control > N2 > recov(

3*4+ 0.7*2-9+0-855+8*

237 + 1201-3+0-6186+ 16

n.s.

n.s.

n.s.

n.s.

n.s.

n.s.

* n reduced by 1 for these values. n.s. = not significant. Abbrevi-

with 02 As expected, arterial 02 content nearly doubled (7'3 to 14-7 ml dl-1) duringventilation (Table 1). Arterial Po2 increased in every fetus, the amount presumablydepending on the degree of pulmonary maturation. Left ventricular stroke volumeincreased in every fetus with changes ranging from 02 to 2-9 ml kg-' with an average

of09 ml kg-'. With 02 ventilation, mean left atrial pressure increased by 7-7 mmHgand right atrial pressure showed a modest 1-5 rnmHg increase. pH and arterial bloodpressure did not change during 02 ventilation. As in our previous studies (Thornburg

PHY 383

n

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M. J. MORTON AND OTHERS

& Morton, 1983), heart rate increased after the first function curve even in thepresence of cholinergic and f-adrenergic blockade.N2 ventilation had little effect on the haemodynamic and blood gas variables that

we measured (Table 2). The fetus became somewhat acidotic while being ventilatedwith N2 but without a change in PCo2. Arterial Po2 and 02 content decreased.

A B1*5 - 20 -

E 1502 ~~~~~~~~~~~~E

E10 Ca''Sal0

M ~~~~~~~~~~~~~~~~~~~~~~~~02

U 0

0 5 10 15 20 0 5 10 15 20Mean left atrial pressure (mmHg) Mean right atrial pressure (mmHg)

Fig. 2. Fetus VI, 3 0 kg. A, left ventricular function curve before (0) and during (El) 02ventilation. Best-fit regression lines are forced through points above and below mathe-matically determined intersection filling pressure (Thornburg & Morton, 1986). For anygiven mean left atrial pressure stroke volume was greater during 02 ventilation. Prior tochanging blood volume, the normal operating mean filling pressure in this fetus wasapproximately 4 mmHg before ventilation and approximately 14 mmHg during venti-lation. B, mean left atrial pressure plotted as a function ofmean right atrial pressure during' control' (0) and '02 ventilation' (El) function curves. Best fit line under control condi-tions was Pi a = 0-93 Pr a + 1-1, r = 10 and Pi a = 3*5 Praa3*0, r = 0 99 during O2venti-lation, where PI a and Pr a are mean left and right atrial pressures (mmHg). See text forPla-Pna composite analysis.

Recovery data show (Table 2) that most of the large changes associated withventilation returned to their pre-ventilation level after ventilation had ceased. 02content decreased to a value lower than the original control value. Blood gas andpH values suggest some deterioration of the fetus; arterial pH and P02 were lowerthan control and arterial PCO, was elevated. After the conclusion of ventilation,fetuses were not followed for sufficient time to determine their eventual course ofrecovery. But two fetuses, re-studied two days after initial ventilation, returned totheir normal condition (K. L. Thornburg & M. J. Morton, unpublished observation).

Control left ventricular function curves were similar in shape to those found in ourprevious studies of the right (Thornburg & Morton, 1983) and left (Thornburg &Morton, 1986) ventricles, and similar to fetal cardiac function curves generated inother studies (Downing, Talner & Gardner, 1965; Gilbert, 1980). The curves werecharacterized by a steep ascending limb and a plateau limb with a distinct

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02 VENTILATION AND FETAL L. V. STROKE VOLUME

intersection (Fig. 2). As shown in previous studies, the sheep fetus normally maintainsits filling pressure and stroke volume at the intersection of the two limbs of thefunction curve (Gilbert, 1980; Thornburg & Morton, 1983, 1986). Fig. 2 shows twofunction curves from fetus VI, one before and one during ventilation with 02* In thisanimal, as with others, the function curve shifted obviously upward in response to02 ventilation so that left ventricular stroke volume was larger than control for anygiven filling pressure.

2 5

20

0

EVS

01- -0 1s 2

0

10-

CaW

0> Q.5

0

0 5 110 15 20Mean left atrial pressure (mmHg)

Fig. 3. Composite left ventricular function curves for eight fetuses before (0) and during(L) 02 ventilation. The function curve for each fetus was significantly elevated (P < 005)during 02 ventilation. For all curves, the mean stroke volume at the intersection was1-3 + 0-7 ml kg-' before ventilation and 2-1 + 1-3 ml kg-' during ventilation at mean leftatrial pressure of 3-4+ 1-5 and 3-6+ 1-5 mmHg, respectively. The average ascending andplateau slopes were 029+ 0-21 and 003 + 004 ml kg-' mmHg-' for the control curve and049 +0O38 and 0-01 +0O02 ml kg-' mmHg-' for the 02 ventilation curve.

Composite control and 02 ventilation function curves from all eight animals areshown in Fig. 3. As for the individual fetus shown in Fig. 2A, the composite 02ventilation function curve was dramatically elevated above the control curve(Fig. 3). The ascending and plateau limbs were analysed separately by analysis ofcovariance. Each limb (y-adjusted means) was significantly elevated duringventilation (P < 0 05). The mean intersection stroke volume increased from1-3 + 0 7 ml kg-' in the control to 2-1 + 1-3 ml kg-' in the ventilated condition.However, the filling pressure at which the intersection occurred was not changed by02 ventilation, being 3-5+ 1-5 mmHg under control conditions and 3-6 + 1-5 mmHgduring 02 ventilation. The slopes of the ascending and plateau limbs of the functioncurves could not be shown to have changed during ventilation (Fig. 3, legend). Therewas no significant relationship (P > 0-05, linear regression) between the percentageincrease in stroke volume and either P02 increase or 02 content increase (Table 3).Changes in stroke volume with 02 ventilation were rapidly reversible and repeatable.As mentioned above (Table 1), mean left atrial pressure increased with 02

14-2

419

M. J. MORTON AND OTHERS

ventilation. In fetus VI, shown in Fig. 2, mean atrial pressure increased from 4 mmHgbefore ventilation (which coincides with the intersection pressure of its controlfunction curve) to 14 mmHg during ventilation. The latter pressure was well out onthe plateau limb of the 02 ventilation function curve. Fig. 2B shows that therelationship between mean left and right atrial pressures for fetus VI was quite

TABLE 3. Effect of 02 ventilation on stroke volume, PO2, 02 content and atrial pressures

Percentageincrease* Increase Increase in Slopestroke in PO2 02 content l.a.-r.a.

Fetus volume (mmHg) (ml dl1) relationshipI 58 14 1-6II 18 43 7-1III 35 2 1-3 3-1IV 47 23 5-7 6-8V 28 246 9.9 1-2VI 50 53 9.7 3-5VII 30 317 10 0VIII 32 49 8-2 3-0

Linear regression of column 1 on 2, r =-0-41; 1 on 3, r = -0 07; 1 on 4, r = 0-22; all P > 0 05.* Percentage change in stroke volume was calculated from the y-adjusted means of the stroke

volumes from the plateau limb of the function curve to reduce independent effects of left atrialpressure.

PO2 = partial pressure of 02 in the carotid artery. l.a.-r.a. slope = slope of linear regression ofleft atrial on right atrial pressure during 02 ventilation.

different during ventilation. This change in left-right atrial pressure relationship wasfound in all fetuses where 02 ventilation was effective in changing arterial PCo2, butwas not present during N2 ventilation. In the six animals where simultaneous reliableleft and right mean atrial pressures could be recorded, the average regressioncoefficient of the relation between mean left atrial and mean right atrial pressure was1-01+0 16, r = 0-99 + 001 before ventilation and significantly increased (P < 0 05) to3-20+ 1t99, r = 0-96 + 0 04 during ventilation. These data indicate that, on average,left atrial pressure was three times greater than right atrial pressure during in uteroventilation with 02 over the range of pressures studied. There was no significantrelationship (P > 0 05, linear regression) between percentage increase in strokevolume during 02 ventilation and the slope of the relationship between left and rightatrial pressure (Table 3).

DISCUSSION

To our knowledge, the haemodynamic effects of pulmonary respiration in uterohave not been previously reported. The present study shows unequivocally thatneonatal levels of left ventricular stroke volume and output can be attained in thefetus ventilated with 02, but not with N2. Furthermore, the increased output isassociated with the development of a left-right atrial pressure gradient as well asincreased arterial 02 content and occurs in the presence of /J-adrenergic blockade.The implication that in utero ventilation mimics the normal birth process requires

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02 VENTILATION AND FETAL L. V. STROKE VOLUME

qualification. We assume that placental flow remains intact during in utero ventilationwhile flow through the ductus arteriosus may be reversed. Foramenal flow probablyceases as evidenced by the high carotid artery Po2 and the pressure gradient acrossthe atrial septum. In these experiments, positive pulmonary ventilation wassubstituted for normal spontaneous respiration. Willis et al. (1985) reported smallchanges in central venous and arterial pressures with in utero ventilation. However,we doubt that the haemodynamic and respiratory effects of ventilation which aredifferent from normal birth importantly affect the results of in utero ventilation withrespect to the shape or position of the left ventricular function curve.Many factors have been suggested to cause increased left ventricular output at

birth: increased 02 consumption, haemoglobin changes, altered metabolic pathways(Klopfenstein & Rudolph, 1978), thyroid hormone, catecholamines (Riemen-schneider, Brenner & Mason, 1981), and increased end-diastolic volume (Anderson,Glick, Manring & Crenshaw, 1984). It is clear that increased left ventricular strokevolume at birth is an important contributor, along with increased heart rate, toincreased output. The present study shows that the increase in stroke volume within utero ventilation is rapid and reversible, changing too quickly to be due to theeffects of thyroid hormones. In addition, Breall, Rudolph & Heymann (1984) havedemonstrated that thyroidectomy does not change stroke volume during thetransition. We have confirmed the findings of Klopfenstein & Rudolph (1978) thatcompetitive f-adrenergic blockade does not alter this response. Because strokevolume is the product of end-diastolic volume and ejection fraction, one or both ofthese parameters must change dramatically with 02 ventilation in utero and at birth.The results presented in this study do not justify favouring one mechanism (volumeor shortening) over another. Definitive statements regarding mechanisms must awaitthe measurement of fetal left ventricular volumes and ejection fraction during in uteroventilation with 02.The increased left ventricular end-diastolic dimension noted at birth by Anderson

et al. (1984) in seven lambs and Kirkpatrick, Covell & Friedman (1973) in one lambprovides circumstantial evidence that increased end-diastolic volume may play animportant role in the transitional increase in stroke volume. Yet, why were we unableto increase stroke volume much above control values by increasing filling pressurebefore ventilation in these eight and seventeen previously studied animals (Thorn-burg & Morton, 1986)? The answer may lie in Fig. 2; the function curve is shiftedupward. In addition to contractility and after-load, diastolic pressure-volumerelations are an important determinant of the position of the function curve whenfilling pressure is used as the independent variable (Glantz & Parmley, 1978).

Therefore, we should not ignore the profound change in the relationship betweenright and left atrial pressure which occurs after pulmonary ventilation with 02.Ventricular interdependence, the effect of contralateral ventricular pressure on strokevolume, is well established in the hearts of adult animals (Elzinga, van Grondelle,Westerhof & van den Bos, 1974) and has been studied in new-born piglets (Versprille,Jansen, Harinck, van Nie & de Neef, 1978). We are unaware of studies of ventricularinterdependence in unanaesthetized fetuses, although Wladimiroff, Vostess & McGhie(1982) have studied right and left ventricular stroke volume in fetal and new-borninfants using ultrasonic imaging techniques. The data of Romero, Covell & Friedman

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M. J. MORTON AND OTHERS

(1972) indicate, however, that left ventricular volume in the arrested fetal lamb heartis clearly dependent upon right ventricular pressure and this dependence is morepronounced in fetal than new-born or adult hearts. Definitive studies regarding theeffect of right ventricular pressure on left ventricular volume in the fetus need to beperformed and resultant effects on stroke volume determined. The change seen in thefunction curve with in utero ventilation might be explained by the establishment ofa left-right atrial pressure gradient which results in a degree of left ventriculardistension not possible under normal fetal conditions where filling pressures are equal.

Ejection fraction might increase because of increased contractility or reducedafter-load. Because systemic pressure is increased or unchanged at birth or duringin utero ventilation, it is unlikely that after-load is reduced. Increased shorteningthrough increased contractility seems the obvious solution to the increase in leftventricular stroke volume. Support for this view comes from several studies of indicesof contractility which are clearly increased in the lamb at birth (Berman &Musselman, 1979; Riemenschneider et al. 1981; Anderson et al. 1982, 1984).Anderson's very difficult studies measured left ventricular dP/dt and minor axisdimension shortly before and after birth in chronically instrumented fetal lambs.They concluded that increased end-diastolic dimension, shortening, and heart rateall contributed to increased left ventricular output at birth. Increased contractilitywas suggested by increased maximum dP/dt and increased fractional shortening.Heart rate was not responsible for the increases in these indices; however, neitherthe fetus nor the neonate received adrenergic blocking agents. In addition, theauthors showed convincingly the pre-load dependence of dP/dt and fractionalshortening. Unknown, then, is the extent to which real changes in contractilitypromote shortening at birth and the role which 02 might play in augmentingcontractility.The suggestion that increased coronary artery 02 content might increase contrac-

tility is contrary to what is known about the function of the adult heart. Downey(1976) has shown that increases in coronary flow above the autoregulatory set pointprovide minimal augmentation of contractile force. Fisher (1984), reviewing hisextensive investigations of oxygenation and metabolism in the developing heart,showed that the fetal heart is neither anaerobic nor maximally vasodilated. Fetalmyocardial 02 consumption does not decrease despite a substantial experimentaldrop in arterial 02 content. It does not appear that 02 availability limits fetalmyocardial performance under base-line conditions. Therefore, if 02 were to play arole in increasing contractility at birth, it would need to release a contractile reservewhich was otherwise unavailable to the normoxic fetus.The rapid and reversible establishment of a left-right atrial pressure gradient with

02 but not N2 ventilation is of interest. Cassin, Dawes, Mott, Ross & Strang (1964)showed that the increase in pulmonary blood flow at birth was dependent onmechanical ventilation and, more importantly, on release of hypoxic pulmonaryvasoconstriction. It is likely that pulmonary blood flow, which becomes left ven-tricular inflow, increases tremendously in these experiments during 02 ventilation.Thus, the effect of 02 on the resistance vessels of the pulmonary vasculature may becritical in the augmentation of left ventricular stroke volume at birth.

422

02 VENTILATION AND FETAL L. V. STROKE VOLUMEThe authors are grateful for the technical assistance provided by Thomas Green, Dana McNaught,

Cindy Machida, and Robert Webber. Jackie Niemi provided expert manuscript preparation. DrsD. F. Anderson, J. Metcalfe, and C. Parks provided various assistance and counsel. Without DrJ. Job Faber, who loaned us equipment, personnel and advice, this work would not have beenpossible. Supported by N.I.H. grant HL 29324. Dr Pinson was a research fellow of the AmericanHeart Association, Oregon Affiliate.

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ANDERSON, D. F., BISSONNETTE, J. M., FABER, J. J. & THORNBURG, K. L. (1981). Central shuntflows and pressures in the mature fetal lamb. American Journal of Physiology 241, H60-66.

ANDERSON, P. A. W., GLICK, K. L., MANRING, A. & CRENSHAW JR, C. C., (1984). Developmentalchanges in cardiac contractility in fetal and postnatal sheep: in vitro and in vivo. AmericanJournal of Physiology 247, H371-379.

ANDERSON, P. A. W., MANRING, A., GLICK, K. L. & CRENSHAW JR, C. C. (1982). Biophysics of thedeveloping heart. III. A comparison of the left ventricular dynamics of the fetal and neonatallamb heart. American Journal of Obstetrics and Gynecology 143, 195-203.

BERMAN JR, W. & MUSSELMAN, J. (1979). Myocardial performance in the newborn lamb. AmericanJournal of Physiology 237, H66-70.

BREALL, J. A., RUDOLPH, A. M. & HEYMANN, M. A. (1984). Role of thyroid hormone in postnatalcirculatory and metabolic adjustments. Journal of Clinical Investigation 73, 1418-1424.

CASSIN, S., DAWES, G. S., MOTT, J. C., Ross, B. B. & STRANG, L. B. (1964). The vascular resistanceof the fetal and newly ventilated lung of the lamb. Journal of Physiology 171, 61-79.

DOWNEY, J. M. (1976). Myocardial contractile force as a function of coronary blood flow. AmericanJournal of Physiology 230, 1-6.

DOWNING, S. E., TALNER, N. S. & GARDNER, T. H. (1965). Ventricular function in the newbornlamb. American Journal of Physiology 208, 931-937.

ELZINGA, G., VAN GRONDELLE, R., WESTERHOF, N. & VAN DEN Bos, G. C. (1974). Ventricularinterference. American Journal of Physiology 226, 941-947.

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