Review Article

Arch. Dis. Childh., 1965, 40, 575.

THE LUNGS AT BIRTHBY

L. B. STRANGFrom the Department ofPaediatrics, University College Hospital Medical School, London

(RECEIVED FOR PUBLICATION JUNE 20, 1965)

In order to obtain insight into disturbances ofpulmonary function in newborn infants we have toconsider the physiological changes that occur in thelungs at birth. By combining the informationobtained from a variety of animal experiments withour clinical observations, we can construct a fairlycoherent picture of some of these events and see theways in which their normal course is disturbed bydisease. The first breath of air also marks thebeginning of individual life, an abrupt change in themode of external respiration, and it stands in its ownright as a subject of general interest.The ultimate exchange of oxygen and carbon

dioxide between cells and their environment occursby molecular diffusion, but multicellular formsrequire a specialized organ of external respirationsuch as gills, placenta, or lungs, to and from whichthe gases are transported by a circulation. Duringfoetal life the infant's gases exchange in the placentabetween two liquids, the maternal and foetal bloods,but from the moment of birth this function istransferred to the lungs where the exchange isbetween liquid and gas. In this sense the evolution-ary development from water to air is re-enacted eachtime an infant is born.The foetal lungs are functionally inert. The

alveoli are filled with liquid, and they are perfused byonly 10% of the cardiac output. For the lungs toacquire their function as a gas exchanger a numberof changes must take place. A gas-liquid interfacehas to be formed and the alveoli have to acquire avolume of gas which remains in the lungs even at theend of an expiration, and can be exchanged with theatmosphere by the movements of ventilation. It isalso fundamental for normal gas exchange that thegas volume should be evenly distributed throughoutthe lungs. As the gas that enters the foetal lungsoccupies a space formerly filled with liquid, we alsohave to consider how this liquid is removed.

On the other side of the interface a large increasein blood flow is required. Although the rates atwhich gases equilibrate in the lung depend on thearea, thickness, and composition of the tissues lyingbetween the gas and blood, the amounts exchangeddepend on the flow of blood through the lungs. Inthe adult, pulmonary blood flow equals rightventricular output, but in the foetus most of thecardiac output bypasses the lungs. At the start ofbreathing an increase in pulmonary flow is achievedby a change in the distribution of cardiac output.

These various changes are all a consequence of thefirst breath of air, which depends on the activity of therespiratory muscles and the nervous system. Thepresent account, however, is confined to events in thelungs. The formation of an alveolar gas volume,the removal of liquid from the foetal lungs, and theincrease in pulmonary blood flow are functionallylinked, but they can be separated for descriptivepurposes.

Formation of Alveolar VolumeFIG. IA shows the relation between inflating

pressure and lung volume when the lungs of a maturefoetal lamb are inflated with air through the trachea.The same relationships apply when the inflatingpressure is a negative pleural pressure and have beenverified in a variety of other species. Duringinflation, an opening pressure of 18 cm. H1O isrequired before any air enters the lungs and then theyinflate readily to their full volume with only a smallfurther increase in pressure. The deflation curve iswidely separated from the inflation curve, and ateach pressure much more air remains in the lungduring deflation than during inflation. Even atzero pressure about 25% of the lung volume remains.The second inflation of this lung is different becauseno opening pressure is now required and the lunginflates to 80% of its volume at a pressure that was

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L. B. STRANG

00

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0

0'a

A B

10 20 30 40 10 20 30 40PRESSURE cm.H20

FIG. 1A.-Relationship between inflating pressure and the volume of gas in the lung during the first and second inflation of the lungs of alamb of 140 days' gestation (term = 147 days). The first inflation and deflation are shown with a solid line, the second with an interrupted

line. Direction (whether inflation or deflation) is indicated by arrows.FIG. IB.-Inflating pressure and gas volume of the lungs of a lamb of 122 days' gestation. In this case there is no difference between the first

and second inflations.

insufficient to open it for the first time. Fig. lBshows the relationship for an immature lamb. Theinflation curve is similar to Fig. IA, but the deflationlimb is closer to the inflation curve, and at zeropressure the lung is empty of air. For this reasonthe lung has to be reopened with the second breathand with each succeeding breath. Figs. 2A and 2Brepresent these curves pictorially as steps in theinflation and deflation of an imaginary alveolus.Thus in the mature lung a stable alveolar volume

(Functional Residual Capacity-FRC) is formedafter the first inflation, and normal ventilation canproceed with relatively small pleural pressurechanges. Each succeeding tidal breath exchanges

-- INFLATION --

about 30% of this FRC for fresh air (Strang andMcGrath, 1962), while oxygen and carbon dioxideexchange continuously between the gas and blood.In the immature lung, as almost no FRC is formed,ventilation requires abnormally large pressures toopen the lungs with each new breath, and it seemslikely that gas exchange can take place only duringinspiration, while the alveoli are held open, insteadof during the whole ventilatory cycle. A dynamicpicture of ventilation in these two types of lung canbe obtained by watching the surface of a lamb's lungduring positive pressure ventilation. In the maturelung the first inflation converts the liver-like lung ofthe foetal lamb to the pale pink inflated appearance

[-INFLATION"-"- .

0o- 0 0L5I20MATURE IMMATURE

15 2TS 0 0 : 15 20.;3.x0 EFLATION-VW-. DEFLATION

Fio. 2A.-Pictorial representation of stages during the initial inflation and deflation of an imaginary alveolus in a mature lung such as thatrepresented in IA. The alveolus is pictured as being filled with liquid (shaded) before air enters it, and the air is accommodated partly by

displacement of the liquid. Numbers indicate inflating pressure in cm. H20.Fio. 2B.-Inflation and deflation of imaginary alveolus from immature lung such as that represented in lB.

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THE LUNGS AT BIRTH

characteristic of normal lungs, and during deflationthis appearance is retained. By contrast the imma-ture lung has the inflated appearance only at the peakof inspiration and returns to the foetal appearanceduring each expiratory phase.The formation of a stable FRC in the mature lung

can be explained by the properties of the surface filmwhich forms in the alveoli. The alveoli of thenormal lung are lined by a lipoprotein film which oncompression has a very low surface tension, andprevents the alveoli from collapsing under thepressure generated by their surfaces (Pattle, 1955).To understand this statement we have to consider theeffect of surface tension at a curved interface. Themolecules of a liquid exert an attracting force on eachother. At any depth in the liquid these forcesbalance, but at the surface there remains an un-balanced intermolecular attraction which creates thesurface tension. The effect of this force is to pullthe surface to as small an area as possible. Whenthe surface is curved, surface tension will exert aforce in the direction of the radius. In a sphere, forexample a bubble in water, surface tension willproduce a pressure difference across the wall. Therelationship between the pressure generated in asphere by the tension in its wall is given by an

expression of La Place, P = y (where P is pressure,r

y is tension, and r is radius). Consider an alveolusinto which air has been forced by the first inspiration.If the air space which is formed is spherical with aradius of 5 x 10-3 cm. and the surface tension is55 dynes/cm. (the surface tension of most bodyfluids), the surface will exert a pressure of 22* 5 cm.H20. In other words a negative pleural pressure ofthis amount would be required to hold the spaceopen, and during expiration, when the inspiratorymuscles are relaxed, the space would collapse. Inthe mature lung a surface film of lipoprotein isformed as soon as air enters the lung which, whencompressed, yields a very low surface tension,probably of the order of 1-5 dynes/cm., whereasthe same film when stretched gives a surface tensionvalue of about 50 dynes/cm. (Clements, Brown, andJohnson, 1958). During inspiration, while thealveoli are enlarging, a considerable pressure isgenerated by the lung surface, but as soon asexpiration starts and the alveolar surface is compres-sed a little, the surface tension falls and the retractivepressure generated by the surface becomes muchless. For example in the alveolus considered above,a surface tension of 1 dyne per cm. would yield apressure of about 0'5 cm. H20. The presence oflipoprotein (surfactant), which forms a film withthese special characteristics, explains the pressure-

volume characteristics of the lung illustrated inFig. IA, and in particular the small pressure genera-ted during deflation. The surfactant material couldnot be demonstrated in the lung illustrated in Fig. I B,which accounts for its different behaviour duringdeflation, including the failure to form an FRC.

Surfactant also tends to stabilize the distributionof air in the lungs. Because of the relationshipbetween pressure and radius in the La Place equation,smaller alveoli would develop a higher pressure thanlarger alveoli and tend to empty into them, if thesurface tension remained constant. However, as analveolus decreases in size, its lining film becomesmore compressed and its surface tension falls, thustending to equalize the pressures in alveoli of differ-ing size and consequently to equalize the alveolarsizes themselves.

Thus, the formation of a stable alveolar volume,and its equal distribution in the lungs, depends onthe special properties of the surface film which isformed in alveoli when air first enters the lung. Thelipoprotein from which the film is formed is probablypresent in functionally adequate amounts from about30 weeks' gestation onwards in the human, but itappears relatively later in the gestations of lambs,rabbits, and mice. (For a review of this questionsee Strang and Reynolds, 1965.)

Removal of Liquid from the LungsThe lungs of the foetus contain clear liquid which,

in the foetal lamb, pours readily from the cut end ofthe trachea or bronchus. Its volume is about 50 ml.in a foetal lamb of 3-5 kg. (Howatt, Humphreys,Normand, and Strang, 1965), which is similar to thealveolar gas volume (FRC) in infants of similarweight (Strang and McGrath, 1962). Indeed theresting volume of the lungs, which depends on theposition where the elastic recoil of the lungs isbalanced by the elastic recoil of the chest wall, shouldbe very similar before and after a breath of air if thesurface force is small. With a large surface forcethe gas volume should be smaller than the liquidvolume. Setnikar, Agostoni, and Taglietti (1959)and Adams and Fujiwara (1963) have shown that thelung liquid differs in composition from amnioticliquid and contains much less bicarbonate than ablood transudate, from which we may deduce that itis a lung secretion.Where does the liquid go when breathing starts?

Some can be squeezed out through the mouth duringthe second stage of labour, or drain by gravity whenthe newborn infant is held head down. The amountthat remains in the lungs must vary with the circum-stances of delivery and should be greatest aftercaesarean section. As the survival of mature

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L. B. STRANGinfants after this mode of delivery is as good as aftervaginal delivery (Strang, Anderson, and Platt, 1957)the volume drained from the lungs is probablyunimportant for survival. The remaining fluid mustbe taken up when breathing starts, but there havebeen no direct studies of the rate at which this takesplace. The mean weight of mature lambs' lungsfalls by about 50 g. during the first six hours of lifeand then no further, suggesting that the liquid iscleared in this period (author's unpublisheddata). The liquid is usually assumed to be absorbeddirectly into the blood, but no change that wouldfavour this transfer, such as a fall in pulmonarycapillary pressure, is known to occur. Indeed thepulmonary vasodilatation at the onset of breathingshould cause a rise in capillary pressure, if, as seemslikely, the change in vasomotor tone is in precapillaryarterioles.

Recent experiments have shown that a largeincrease in lymph flow from the lungs accompaniesthe onset of ventilation in mature lambs, and itseems likely that some of the lung liquid is clearedfrom the lungs by this route (Boston, Humphreys,Reynolds, and Strang, 1965). The mechanismenvisaged is that air entering the alveoli displacesliquid (as in Fig. 2A) into the interalveolar spaces ofthe lung where lymphatic capillaries are abundant.A similar mechanism for the removal of lung liquidwas suggested by Aherne and Dawkins (1964) fromthe histological appearance of rabbits' lungs.Boston et al. (1965) found a much smaller increase oflymph flow at the onset of ventilation in immaturelambs. In the immature lung it may be thatabnormally high surface tensions cause the alveoli tofill up with liquid during expiration (as pictured inFig. 2B) and impede the transfer of liquid to theinteralveolar spaces.

Increase in Pulmonary Blood FlowDuring foetal life most of the inflow from the great

veins bypasses the lungs. About half the flow fromthe inferior vena cava passes directly through theforamen ovale to the left atrium, the left ventricle,and the aorta. The remaining inferior vena cavalflow and the superior vena caval flow enters the rightatrium, right ventricle, and pulmonary artery.From the pulmonary artery most of the flow goes tothe aorta through the ductus arteriosus, and only asmall fraction (say 10%) passes through the lungs.This distribution depends on the vascular resistancein the lungs being higher than the systemic vascularresistance. Dawes, Mott, Widdicombe, and Wyatt(1953) showed that a large decrease in pulmonaryvascular resistance occurred when the lungs werefirst ventilated and that pulmonary blood flow

increased by a factor of 5 or 10. Closure of thevalve of the foramen ovale by a rise in left atrialpressure above inferior vena caval pressure is aconsequence of the increased inflow to the leftatrium from the lungs. Closure of the ductusarteriosus occurs by active constriction of themuscle in its wall, which contracts in response to arise in the oxygen tension of the arterial blood leavingthe newly ventilated lung. For a review of thesechanges see Dawes (1958). Thus all the changes inthe circulation depend on the decrease in pulmonaryvascular resistance at the onset of ventilation, andhence it is important to determine by what meansthe vascular resistance is lowered.

In experiments that aim to compare the vascularresistance of the lungs under various conditions,serious difficulties of interpretation may arise becausethe relationship between pulmonary artery pressureand flow is non-linear. Fig. 3 shows two pressure

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PAP-LAP (cm.H20)40

FIG. 3.-Pressure flow curves of the vasculature of the left lung of alamb. Curve B was obtained during lung collapse and curve Aduring ventilation with air. The curves were obtained by perfusingthe lung at a series of pulmonary artery pressures (PAP) while leftatrial pressure (LAP) remained steady. As shown, calculated'resistance' (R), obtained by dividing pressure by flow, gives lowervalues at a high PAP than at a low PAP. In one set of experimentsdifferences such as that between curves A and B were investigated bycomparing the flows at a constant PAP. In another set ofexperimentsthe comparison was made by drawing pressure flow curves using thedevice shown in Fig. 5. In Fig. 6 pressure flow curves have beensimplified by showing straight lines fitted to the steepest part of thecurves. (Reproduced from Cook et al. (1963) by permission of

J. Physiol. (Lond.).)

flow curves for the pulmonary vessels of a lamb. Ifthe relationship were linear through zero, resistance,computed as pressure divided by flow, would be aconstant, but this is not true of these grossly non-linear relations. As shown in Fig. 3, a change inperfusion pressure such as will occur during a changein vascular resistance, unless it is artificially control-led, can cause an apparent change in vascular resist-

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THE LUNGS AT BIRTH5

ance when there is really no intrinsic change in thevessels themselves. For this reason, in the type ofexperiments to be considered now, some device hasto be adopted that will allow comparisons betweenstates of the vasculature, such as those depicted bythe two curves in Fig. 3. There are three possiblesolutions: (i) to hold flow constant by some deviceand compare perfusion pressure, (ii) to hold pressureconstant and compare flows, (iii) to draw some kindof pressure flow curve for each set of conditions. Inthe experiments to be described methods (ii) and (iii)have been used.

Experiments in which the left pulmonary artery ofthe lamb was perfused at a constant pressure showedthat the pulmonary vessels could exhibit an extremelyactive vasomotor tone, and that lowering the oxygentension or increasing the carbon dioxide tension ofthe ventilating gas had a strong vasoconstrictoreffect (Fig. 4) (Cook, Drinker, Jacobson, Levison,

E-i

100

0J 20-

N2100/0CO2

240 260 280TIME FROM DELIVERY (min.)

FIG. 4.-Measurement of left pulmonary artery flow in the lamb at aconstant pulmonary artery pressure of 40 cm. H20. The open circlesare blood flow during ventilation of the lung with air, the closed circlesare flow during ventilation with nitrogen, and the half-closed circlesare flow during ventilation with 10% carbon dioxide in air. Thesharp decreases in flow at a constant perfusion pressure are due topowerful vasoconstriction. (Reproduced from Cook et al. (1963) by

permission of J. Physiol. (Lond.).)

and Strang, 1963). The vasomotor tone of thefoetal lung was also detected by the vasodilatoreffects of acetyl choline and histamine (Dawes andMott, 1962). The vasoconstrictor effect of asphyxialgas tensions could also be produced in the unexpand-ed foetal lung by umbilical cord occlusion (Dawesand Mott, 1962) or by perfusing the lung with bloodof high Pco2 and low Po2 (Cassin, Dawes, Mott,Ross, and Strang, 1964). There was some evidencethat the changes in gas tension were effective mainlyby a direct action on the pulmonary vascular muscle,rather than through chemoreceptors- (Cook et al.,1963).

The Po,and Pco2 of the foetal lung are determinedby the tensions of these gases in the pulmonaryarterial blood. This implies that the areas with thehighest Po5's will have a tension between 20 and 30mm. Hg, and the areas with the lowest Pco,'s, atension between 40 and 50 mm. Hg. Ventilationwith air will raise the highest Po2 areas to over100 mm. Hg and decrease the Pco2 by an amountdependent on the extent to which blood flow increasesin response to ventilation. Plainly the vasodilatationat the onset of breathing could be due to the effectsof changes in gas tensions alone. Sensitivity of thevasomotor tone to Pco5 would, in particular, tend tomatch blood flow to ventilation, because alveolarPco2 is an almost linear function of the ratio ofventilation to perfusion. For example, if a lungwere well ventilated but poorly perfused (high ventila-tion-perfusion ratio), the Pco2 would fall and tend toincrease perfusion by decreasing vasomotor tone.The extent to which the changes in gas tension do

in fact determine the effect of ventilation wasinvestigated by Cassin et al. (1964). In theseexperiments the vascular 'resistance' of the lamb'slung was determined by drawing pressure-flowcurves of the vasculature of the left lung undervarious conditions by the means described in thecaptions to Figs. 5 and 6. The lungs were firstventilated with a mixture of 7% carbon dioxide innitrogen which has gas tensiors very similar to thoseof the blood perfusing the foetal lung. In this waythe effect of ventilation could be tested independentlyof the gas tension changes induced by ventilationwith air. Subsequently, the ventilating gas waschanged to air, or to nitrogen, or to 10% carbondioxide in air, so that the effects of increasing Po2and lowering Pco2 could be measured separately.Fig. 6 gives the maximum slopes of the pressure flowcurves obtained, showing the relative effects ofventilation with 10% carbon dioxide in nitrogen andwith the other gas mixtures. In general, 20% of thevasodilatation was associated with ventilation itself,and the remainder was due in approximately equalamounts to a decrease in Pco2 and an increase inPo2. The means by which ventilation, as distinctfrom gas tension change, causes vasodilatation is atpresent unknown, but the effects of Po2 and Pco2 areclearly identified as vasomotor. Naeye (1961) hasshown that the muscular coat ofpulmonary arteriolesin the foetus is thicker than that of the systemicarterioles, and that this muscle atrophies during thefirst weeks of postnatal life. These arterioles arepresumably the site of the observed vasomotor effects.

In summary, the increase in pulmonary blood flowand the redistribution of cardiac output at the startof ventilation are all due to a decrease in pulmonary

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L. B. STRANG

VERTICALITUBE

FLOW: K) }PRESSURE-

FIG. 5.-Arrangement for obtaining pressure flow curves of pulmonary vasculature in the lamb. The left lung is perfused from the left carotidartery and a vertical tube is placed in the circuit. At intervals this tube is filled with blood and the column of blood is then allowed to flowinto the pulmonary artery while the carotid supply is occluded. By recording pressure and flow on the two axes of an oscilloscope or X-Yrecorder, a graph of flow over a range of pressures is rapidly obtained. Curves of this kind can be drawn repeatedly. (Reproduced from

Cassin et al. (1964) by permission of J. Physiol. (Lond.).)

vascular resistance, which is in large part due to theeffects of changing Po2 and Pco2 on the tone of thepulmonary vessels.

40O

30

E

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10

20

PRESSURE mm.Hq40

FIG. 6.-Mean pressure flow curves of the left lung of the foetal lamb.A straight line has been fitted to the maximum slope of each curve.The lower the vascular resistance, the more vertical the line and themore displaced to the left. The mean curve in the unventilated foetallung is compared with the mean ofthe curves obtained after ventilationwith a mixture of 7% CO2 in N2, with N2, with 7% CO2 in air, andwith air as indicated on the diagram. The effect of ventilationunaccompanied by gas tension change is given by the differencebetween the 'foetal' line and the '7% CO2 in N2 line'. The effect oflowering Pco2 is given by the difference between the '7% CO2 in N2'line and the 'N2' line, or by the difference between '7°% CO2 in air'and 'air'. Similarly the effect of raising Po2 is the difference betweenthe 'N2' and 'air' lines. (Reproduced from Cassin et al. (1964) by

permission of J. Physiol. (Lond.).)

Disturbances of the Physiological Changesin the Lungs at Birth

We have seen that important changes in the lungsat birth can be traced to two events: the formation ofsurface film with special properties and an activevasodilatation of pulmonary vessels. When wecome to consider cardiopulmonary abnormalities inthe newborn we find that the same two factorsdetermine a large part of the abnormalities encoun-tered.

Respiratory Distress Syndrome. Avery and Mead(1959) showed that pulmonary surfactant was absentor inactive in infants dying with hyaline membranedisease. The finding has been confirmed repeatedly(Pattle, Claireaux, Davies, and Cameron, 1962;Reynolds, Orzalesi, Motoyama, Craig, and Cook,1965b), and hyaline membranes have been shown todevelop in immature lambs delivered at 125-130 days'gestation (proportionally equivalent to about 34weeks in humans), when the alveoli are fully formed,but when pulmonary surfactant cannot be detectedby standard techniques (Reynolds, Jacobson,Motoyama, Kikkawa, Craig, Orzalesi, and Cook,1965a). Indeed the absence of surfactant canaccount for all the findings in this condition.Extensive atelectasis due to the surfactant deficiencycauses the low lung compliance (Gribetz, Frank, andAvery, 1959) which in turn leads to ventilatoryinsufficiency (Blystad, 1956; Strang and MacLeish,1961) and to right-to-left shunting (Strang andMacLeish, 1961; Warley and Gairdner, 1962;Prod'hom, Levison, Cherry, Drorbaugh, Hubbell,and Smith, 1962). According to Pattle (1965) thepresence of the hyaline membranes, which are

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mainly a blood transudate (Gitlin and Craig, 1956),can also be explained as an effect of a high alveolarsurface tension which sets up a pressure gradientbetween the air space and the underlying capillaryduring any phase of ventilation in which the alveolusis held open. But variations in capillary permeabil-ity may also be an important factor in determiningthe amount of transudation that occurs. Thedevelopment of respiratory acidosis is due to theunderventilation, and the metabolic acidosis iscaused by anaerobic glycolysis due to a deficientoxygen supply, itself the result of the right-to-leftshunting. The oxygen deficiency may be aggravatedby the excessive oxygen consumption of the over-worked muscles of ventilation.

Since the whole chain of events can start with adeficiency of surfactant, the primary deficiency ofthis substance as a result of immaturity could be thewhole cause of the disease. This theory is supportedby the prevalence of the disease in prematures,perhaps the only really well-established aetiologicalfactor as yet identified, and by the development ofthe disease in immature but otherwise undamagedlambs (Reynolds et al., 1965a). On the other hand,the disease usually develops somewhat after theprobable time of appearance of surfactant in humans(at about 30 weeks), and it seems likely that otherfactors can affect the surface, though this has not yetbeen proved.

Right-to-left Shunting. In general most pulmon-ary disturbances cause cyanosis by impairment ofoxygen diffusion or by inequalities of ventilation withrespect to blood flow. The breathing ofpure oxygeneliminates these effects by massively increasing the

gradient for diffusion and by eliminating the effectsof uneven ventilation on alveolar oxygen tensions(for a more rigorous treatment of these statementssee Berggren, 1942). Therefore, when cyanosis andarterial desaturation persist while the subject isbreathing pure oxygen, it can only be because bloodis passing through unventilated areas of the lungs oris bypassing them through extrapulmonary channels.Newborn infants with ventilatory failure, whether

caused by central depression or impaired lungmechanics, often remain deeply cyanosed even inhigh concentrations of oxygen. In hyaline mem-brane disease the finding of arterial desaturation inthese circumstances is now well established andfirmly attributed to right-to-left shunting. Plainlythe shunting could be through unventilated atelecta-tic parts of the lungs, but, in the lamb at least, bothlung collapse and underventilation cause an increaseof pulmonary vascular resistance, presumablythrough their effect on alveolar gas tensions (Figs. 7and 8) (Cook et al., 1963), and this would shuntblood away from the lungs and particularly from anyatelectatic areas. Thus it seems more likely to thepresent author that the large shunts take placethrough the ductus arteriosus and foramen ovale,i.e. that the circulation returns towards its foetaldistribution. Just as a fall in vascular resistancedetermines the change from a foetal to a neonatalcirculation, so will a rise in the resistance reverse theprocess. The finding of Chu, Clements, Cotton,Klaus, Sweet, Thomas, and Tooley (1965), thatexcised lungs of infants dying with hyaline membranedisease have a high vascular resistance, considerablystrengthens this view of the situation. Indeed thereversibility of the circulatory changes at birth, and

.- 2802

0-J

0 40-0

220 240 2b0 280 3600TIME FROM DELIVERY (mm.)

FIG. 7.-Effect of lung collapse in the newborn lamb on blood flow to the left lung at a constant pulmonary artery pressure of 40 cm. H,O.At the start of the record both lungs are being ventilated with oxygen. At the first arrow ventilation of the left lung is stopped while ventilationof the right lung is continued. The left lung collapses because it contains only absorbable gases. At the second arrow the lung is reventilated,and at the third it is collapsed again by the same procedure. Each episode of lung collapse produces a large reduction of blood flow at constant

pulmonary artery pressure, viz. vasoconstriction. (Reproduced from Cook et al. (1963) by permission of J. Physiol. (Lond.).)

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582 L. B. STRANGloo. * D

00~~~~~

01 01o 0.0

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20 60 100

xA (0/o OF CONTROL)FIG. 8.-Effect of changing alveolar ventilation (VA) on blood flow tothe left lung at constant pulmonary artery pressure. The open circlesrepresent changes in tidal volume, the closed circles changes infrequency. Reducing pulmonary ventilation causes a more or lessproportional reduction in blood flow in these circumstances. (Repro-duced from Cook et al. (1963) by permission of J. Physiol. (Lond.).)

their dependence on ventilation of the lungs, meansthat severe hypoxia is. a greater hazard of under-ventilation in the newborn infant than at other ages-a fact that may well be decisive in determining thehigh mortality of respiratory conditions in infants.

SummaryWhen the normal infant starts to breathe there are

at least three important changes in the lungs: theyacquire a stable alveolar gas volume, lose the liquidwith which they were filled in the foetal state, andincrease their blood flow by five or ten times. Theformation of the stable alveolar volume depends onthe properties of the surface film (surfactant) whichforms in the alveoli. The factors concerned in theuptake of liquid are still uncertain. The increasein blood flow is largely due to a decrease in pulmon-ary vasomotor tone brought about by an increase inPo2 and a decrease in Pco2.

Deficiency or inactivation of surfactant leads toatelectasis and all the abnormalities encountered inthe respiratory distress syndrome. Maturity is oneimportant factor in determining the amount ofsurfactant in the lungs at birth.

Underventilation for any reason causes a rise inpulmonary vascular resistance and a tendency toreverse the changes in the foetal circulation at birth,and hence right-to-left shunting is a commoncomplication of respiratory failure in infants.

REFERENCESAdams, F. H., and Fujiwara, T. (1963). Surfactant in fetal lamb

tracheal fluid. J. Pediat., 63, 537.

Aherne, W., and Dawkins, M. J. R. (1964). The removal of fluidfrom the pulmonary airways after birth in the rabbit, and theeffect on this of prematurity and prenatal hypoxia. Biol. Neonat.,7, 214.

Avery, M. E., and Mead, J. (1959). Surface properties in relation toatelectasis and hyaline membrane disease. Amer. J. Dis. Child.,97, 517.

Berggren, S. M. (1942). The oxygen deficit of arterial blood caused bynon-ventilating parts ofthe lung. Actaphysiol. scand.,4, suppl. 11.

Blystad, W. (1956). Blood gas determinations on premature infants.III. Investigations on premature infants with recurrent attacksof apnea. Acta paediat. (Uppsala), 45, 211.

Boston, R. W., Humphreys, P. W., Reynolds, E. 0. R., and Strang,L. B. (1965). Lymph flow and clearance of liquid from the lungsof the foetal lamb. Lancet, 2, 473.

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