Goeffery Dawes, the famous British physiologist has presented the unborn in the following way (1969): "The human fetus has been likened to a spaceman; passive, insulated and preserved from stimuli, which is only half the truth. On the contrary, one could think of the mammalian embryo as a hitch-hiker with a large pack on his back getting into a rather small car; he is a friendly fellow who chatters away all the time and is prepared to do some driving if given half a chance -- he takes you off your route and tells when and where he would like to get out." In the same way, the fetal circulatory system, different as it is from the child's or the adult's, cannot be dismissed with the common term "immature;" it is a system well adapted to the circumstances, and at no stage is there any evidence of any inadequate circulatory competence.
THE FETAL CIRCULATION
The first recorded mention of the fetal cardiovascular system is attributed to Galen who, in the Second Century A.D., described what were later to become known as the foramen ovale and its valve, as well as the ductus arteriosus, and gave some account of their post-natal closure.
Galen writes: "Nature is neither lazy nor devoid of foresight. Having given the matter thought, she knows in advance that the lung of the fetus, a lung still contained in the uterus and in the process of formation and spared continual motion, does not require the same arrangements of a perfected lung endowed with motion. She has therefore anastomosed the pulmonary artery with the aorta, and the left and right atria. . . ."
Falloppio (1561) initiated the special use of the word "placenta" (literally a flat cake or pancake), and three years later, in 1564, a posthumous publication by Vesalius contained the first account of the ductus venosus. In 1626, Spigel, also in a work published after his death, pointed out the absence of any direct communication between the umbilical vessels of the fetus and the uterine vessels of the mother. He also noted the fact that, in the fetus, the two ventricles are of approximately equal thickness, whereas in the adult the left ventricle predominates.
In 1628, William Harvey introduced his concept of the circulation of the blood and included in his treatise the first account of the fetal circulation. The publication of his work heralded the beginning of the use of a dynamic total concept of the cardiovascular system as opposed to the anatomical descriptions of separate individual structures which had been available up to then. Harvey realized that in the fetus the two ventricles work in parallel instead of in series as in the adult. He appears, however, to have denied the existence of any pulmonary circulation at all in the fetus. In the year 1652, Olof Rudbeck demonstrated for Queen Christina of Sweden and her court his discovery of the lymph vessels.
In the seventeenth century, several other capital discoveries in human physiology were made. In 1660, Robert Boyle demonstrated that part of the air is essential to life. The following year, Malpighi produced the first descriptions of capillaries and of terminal airspace' in the lungs. Six years later, Hooke proved that respiration depends on adequate supply of fresh air to the lungs. In the same year, Walter Neddham called the placenta the "uterine lung." Lower (1669) verified experimentally Hooke's postulate and also showed that venous blood owes its dark colour to "loss of air."
In the following centuries, the course of the fetal circulation was a subject of speculation and controversy. The main problems discussed were the distribution of the superior and inferior caval flow through the fetal heart and whether or not there was a significant pulmonary blood-flow. No notable progress in our understanding was made until the modern era of physiological investigation was started in the twentieth century of Pohlman (1909). He injected starch into different fetal vessels and studied the distribution of the granules.
Hugget (1927) found that the oxygen content of carotid arterial blood was greater than that of umbilical arterial blood. In 1928 Kellog initiated experiments in which the fetus was delivered by caesarean section with the fetal and maternal circulation retained and the fetal respiration prevented.
Forsmann, the heroic genius, carried out the first heart-catheterization and angiocardiography on himself standing before a mirror during flouroscopy. The year was 1929. Nobody dared to assist him. These two methods meant an explosive progress in the study of the circulation.
Few men of science have contributed so much to the advancement of physiology in the first half of this century as Sir Joseph Barcroft. One of his many talents was the ability to attract younger colleagues. In 1938, Barcroft and Barron united their experience of fetal physiology with Barclay, Franklin and Prichard's experience in radiography. The combined Cambridge and Oxford teams obtained the first direct records of the course of the circulation in the fetal lamb.
In the concluding portion of their book, The Foetal Circulation, the authors discussed the possibility of (for what was then the future) direct studies of the human fetal circulation. They expressed the opinion that the best hope for the achievement of this lay in the use of angiocardiographic technique suitably modified and refined. Such studies have been carried out in connection with legal abortions and have resulted in a confirmation of the findings in fetal lambs (Lind and Wegelius 1954). They also pointed out the reciprocal relationship between abnormal respiratory adaptation and cardiovascular disturbances in the neonatal period.
However, angiocardiography is not a quantitative technique. It was, therefore, highly desirable to obtain such information. In 1939, Dawes and his associates, working at the Nuffield Institute for Medical Research in Oxford, presented data on the normal distribution of the blood-flow, derived from the oxygen saturation of blood withdrawn simultaneously from various vessels, in the mature fetal lamb exteriorized by caesarean section. Among the many new data presented, it should be mentioned that the total pulmonary blood-flow averages only about 10% of the combined ventricular output. The quantities of blood flowing through the foramen ovale, ductus arteriosus and aortic isthmus are large, between 35 and 45% of the combined ventricular output. About 55% streams through the placenta, which is characterized by low vascular resistance.
The changes in circulation at birth were first described by Dawes and coworkers: the sudden drop in pulmonary resistance with an increase in pulmonary blood-flow; a reversal in the direction of blood-flow through the ductus arteriosus and the closure of the foramen ovale (Born et al., 1954), a result of the greatly increased blood-flow through the lungs to the left atrium (Fig. 1).
The studies of the fetal circulation in lambs and the changes at birth were pursued by Rudolph and coworkers using more physiological methods (1967). They used indwelling catheters and examined the fetal and newborn lambs in utero and in resting state without use, of anesthesia. They could follow the increase in combined cardiac output as well as the changes in actual blood-flow to various organs during gestation.
Rudolph presented fundamental data on the post-natal changes in cardiac output and its distribution. He found that the right ventricle in the lamb fetus in late gestation ejects about two thirds of the combined ventricular output or about 300 ml/kg/min. With the elimination of the placental circulation and the decrease in pulmonary vascular resistance, the right ventricle ejects all its blood into the pulmonary circulation. When the ductus arteriosus closes, this means about 200 ml/kg/min is ejected, an amount similar to that which has passed through the placenta in utero. The left ventricle which prenatally ejects about 150 ml/kg/min, or one-third of the combined ventricular output, increases its output after birth about 25% to 200 ml/kg/min.
THE IMMEDIATE CHANGES IN THE CIRCULATION AT BIRTH
Our concept regarding the pre-natal circulation in humans is based mainly on animal studies. There seems to be little reason to question the validity of the basic pattern of fetal circulation derived from these experiments, and a limited number of observations in the human fetus corroborate these assumptions. The knowledge about the immediate circulatory adaptation to extrauterine life is also largely built on data from prenatal and postnatal animal studies but to a great extent is also based on studies of the human circulation in the postnatal period.
THE ESTABLISHMENT OF PULMONARY VENTILATION
The proper airfilling of the lungs in the immediate neonatal period has two major functions:
1. It will allow for the exchange of 02 and C02, a function carried out in fetal life by the placenta.
2. The dynamic pressure-flow alterations produced by the expansion of the lungs provide the mechanism around which the newborn's circulatory patterns are initiated, maintained, and varied in the transitional period.
These two functions are so closely related that they should not be thought of as two separate processes. The circulatory adjustment represents a total integrated cardio-pulmonary response, upon the smooth and successful accomplishment of which the fate of the newborn depends. That they are considered separately, is done only for the object of clarity.
INITIATION OF BREATHING AND DYNAMICS OF LUNG LIQUID
The fetal lungs are solid organs secreting fluid into the bronchial tree. They extract oxygen from the blood instead of contributing to oxygenation.
It was Jost (1934) from Paris who first provided evidence of the formation of fluid in the fetal lung of the rabbit. When the trachea was ligated, the lungs became distended over a period of time.
Forrest Adams, pediatrician at U.C.L.A., and his team (1963) made extensive animal studies on the production and composition of the lung liquid and found that it differed chemically from amniotic fluid.
Aeration of the lungs is thus not inflation of collapsed empty organs but rather a replacement of intra-alveolar fluid by air. It has been shown by X-ray that the human lungs occupy about the same intrathoracic volume before and after the first breaths (Lind et al., 1966).
Karlberg et al. (1962) demonstrated that during vaginal delivery, the thorax is subjected to pressures up to 95 cm of H2O and some fluid is expressed from the lungs.
There is then an elastic recoil of the thorax which results in aeration of at least the upper airways.
Active inspiration of 30-70 ml is achieved by the first inspiration and most of this air remains to form part of the residual volume of the lungs. This volume increases with subsequent breaths and the functional residual air is 17 ml/kg body weight at 10 minutes, about twice that 20 minutes later, and shows no further increase during the first week (Karlberg et al., 1962).
At birth, a rapid reversal of the direction of lung-liquid flow is essential for smooth transition from placental to pulmonary gas-exchange. Recent studies have shown that removal of liquid from the lungs begins before birth (Lawson et al., 1978; Bland et al., 1979) and that the increase in cathecholamine production during labor stimulates the absorption of lung liquid. Intravenous infusion of epinephrine into late term fetal lambs causes reabsorption of liquid from potential airspaces (Walters and Olver 1978).
Substantial volume of fluid remains in the lungs even after the first breaths and has to be removed. How this happens has been studied in animal experiments by Leonard Strang and his colleagues at University College, London but it is still a matter of discussion. When breathing starts, a transpulmonary pressure-gradient develops which inflates the lungs and displaces residual liquid from the terminal respiratory airspaces into the distensible perivascular tissue spaces surrounding pulmonary blood vessels distant from sites of respiratory gas exchange (Bland et al., 1979). The concentration of protein in the lung tissue drops, thereby increasing the transvascular protein gradient. Strang found a considerable increase in lymph flow, following birth draining of the lung tissue. Bland and his group, working at the Cardiovascular Research Institute in San Francisco have, over the last years, performed a series of studies on the perinatal lung fluid dynamics. In one study (1980), they measured the excess liquid in the lungs of unanesthesized late term fetal lambs before and during delivery. The volume late in the labor was only 5-7 ml/kg of body weight compared to 20 ml/kg before labor. After birth the pulmonary lymph flow increased and the magnitude of drainage this way was found to be 15-20% of the total lung liquid. Thus, most of it is absorbed directly by the drastically increased microcirculation of blood, which expands the effective vascular surface area for fluid exchange in the lungs.
THE ESTABLISHMENT OF THE POST-NATAL PULMONARY CIRCULATION
The high resistance of the fetal pulmonary vascular bed is believed to be localized in the precapillary muscular arterioles which develop a thick muscular coat during the latter part of gestation (Civin and Edwards, 1951). This muscle mass permits them to function as sphincters controlling the volume flow through the lungs. It regresses by about 40% at two weeks of age (Naeye 1961).
Cook and associates (1963) and Cassin and coworkers (1964) stressed the importance of low PO2 in maintaining pulmonary vasoconstriction in the fetus, and the immediate increase in pulmonary blood flow associated with ventilation of the lungs with gas containing oxygen.
Rudolph and Yuan (1966) studied the pulmonary vascular responses to variation in blood oxygen tension and H+ ion concentration levels in newborn calves. They found a curvilinear inverse relationship between pulmonary vascular resistance and arterial Pot. The vasoconstrictive response to hypoxia was markedly enhanced by lowering arterial pH (Fig. 2).
A reduction of pulmonary blood flow is of little consequence in fetal life where oxygenation is carried out in the placenta. In the neonatal period, however, the development of acidosis and hypoxia from any cause can produce pulmonary vasoconstriction which can have serious consequences. In the immediate neonatal period, a fetal pattern of circulation with right-to-left shunting through the ductus arteriosus and foramen ovale will be reestablished, increasing the hypoxia and the pulmonary vascular resistance, thus creating a vicious circle. The relationship between pulmonary vascular resistance, PO2 and pH, was elucidated by Rudolph and Yuan, which has been of fundamental importance for clinical practice in neonatology.
Other factors also tend to reduce the vascular resistance and increase in pulmonary blood flow after birth. Thus, the production of a liquid-gas interface within the minor airspaces creates a surface tension which can contribute to maintenance of lung vessel patency. It has also been demonstrated that the mechanical effect or respiration movement increases the pulmonary blood flow.
Among the various pharmacologically active pulmonary vasodilators in the newborn period, a-blocking agents, Beta2-agonists and prostaglandin 12 (prostacyclin) are worth mentioning (Lock et al., 1979).
THE CLOSURE OF THE DUCTUS ARTERIOSUS
During fetal life, the ductus arteriosus permits the right ventricle to develop pari passu with the left side of the heart, in spite of the very reduced lung perfusion. It is questionable if the left-to-right shunt which starts with the abrupt reduction in pulmonary vascular resistance is necessary or even meaningful for the postnatal pulmonary circulation. The shunt can be looked at as an additional help to establish an adequate perfusion of the lungs and also as a safety-valve for sudden increase in pulmonary vascular resistance, which otherwise could jeopardize the function of the right ventricle. It must, however, be stressed that the existence of a wide communication between the systemic and the pulmonary circulation carries a risk of volume overloading the left heart from hyperfusion of the lungs, in view of the fact that the left ventricle in late fetal life is used to handle only one-third of the combined ventricular output. An effective synchronization of the drop in pulmonary vascular resistance and the reduction in caliber of the duct seems a prerequisite for prevention of left ventricular failure. Fig. 3 summarizes the resistance in the systemic and pulmonary circulation and the size of the shunt through the ductus. The fact that hardly any shunt can be detected 20 hours after birth, in spite of a resistance ratio between systemic and pulmonary circulation on the order of 2:1, denotes that the ductus is functionally closed (Wallgren 1977). Numerous studies have demonstrated that the duct constricts in response to a variety of stimuli but most researchers agree that the duct constricts at birth primarily in response to high PO2, which was first demonstrated by Kennedy and Clark (1941) at Vanderbilt University.[38,39]
The original demonstration by Coceani and Olley (1973) that E-type prostaglandins are potent relaxants of the ductus arteriosus, confirmed by subsequent animal studies by others, in vitro (Starling and Elliott 1974) and in vivo (Sharpe and Larsson 1975), suggested their use in those cases of congenital heart diseases was entirely dependent on persistence of the ductus arteriosus for the maintenance of pulmonary blood flow. On the other hand, indomethacin, a blocker of prostaglandin synthesis in tissues, produces intense and persistent contraction of the ductus arteriosus in vivo (Sharpe et al., 1974) (Fig. 4). Indomethacin has, since then, been widely used clinically and has proven an effective treatment when used on correct indications.
It is important to point out that the efficiency of ductal closure is related to the maturity of the newborn and persistent patency is a common finding in the premature infant, often complicating the transition to extrauterine life.
CLOSURE OF FORAMEN OVALE
The foramen ovale is the main route for relatively direct passage of blood from the placenta to the brain and normal development of the left heart depends on patency of the foramen.
The closure of the foramen ovale is a consequence of the hydrostatic condition following the increased lung perfusion. Because of the initially small differences in the systemic and pulmonary vascular resistance, and since the central circulatory pattern of the newborn infant is labile-relatively small changes in pulmonary vascular resistance will provoke relapses into fetal circulatory pattern with ductal and/or atrial right to left shunting and arterial desaturation.
Although functional closure is a rapid process (Fig. 5), which may even occur with the first vigorous cry, anatomical closure is a slow process which only exceptionally is complete at three months and usually takes a year or more. Probe patency is seen in more than 50% of children up to five years of age and in about 20% of adults.
PERINATAL SYMPATHO-ADRENAL ACTIVITY
The cardiorespiratory adaptation at birth demonstrates the great capacity of the neonatal circulation to cope with all the strains involved in the reorganization of the circulatory system postpartum. Such a capacity suggests the existence of an effective system of integrated baroreceptor and chemoreceptor reflexes (peripheral and central).
It seems fair to state that the birth process constitutes a major challenge to mechanisms controlling circulatory hemostasis in the newborn. One function of the sympatho-adrenal system is to sustain homeostasis in the newborn. Another function of the sympatho-adrenal system is to sustain homeostasis during stress, and it is not surprising that a strikingly increased activity of this system has been recorded during birth. Lagercrantz et al., (1980) have recently reviewed the sympatho-adrenal activity in the fetus during delivery and birth.
In the fetus and the preterm infants the sympathetic nervous system might not be fully developed (Friedman 1973)45 but the adrenal medulla is relatively voluminous (Comline et al., 1966). The fetus is also provided with paraganglia containing a considerable amount of catecholamines. Studies on previable human fetuses have demonstrated that hypoxia causes a depletion of these paraganglia prior to that of adrenal medulla (Hervonen et al., 1972).
Adrenaline and particularly the noradrenaline concentrations are high at birth after normal vaginal delivery, reaching levels ten times higher than in the resting adult and also considerably higher than in the mother during labor (Lagercrantz and Bistoletti 1977). In asphyctic infants the values are extremely high, probably because hypoxia and acidosis trigger their release, as has been proven the case in laboratory fetuses (Jones et al., 1975) (Fig. 6). The squeezing of the infant, particularly the head, in the birth canal seems to stimulate their release, since very high values were seen in vacuum extracted infants even in those without asphyxia. Furthermore, the catecholamine concentrations seen after selective caesarean sections are considerably lower than after uncomplicated vaginal deliveries, probably due to lack of mechanical stress (Fig. 7).
The concentration of catecholamines in peripheral venous blood remains fairly high during the first three hours after birth. Twelve to 24 hours postnatally, the concentration decreases to normal resting values in adults (Eliot et al., 1978).
Catecholamines are certainly an asset to the newborn. They help to redistribute the blood preferentially to the most vital organs-the placenta, the heart and the brain (Dawes 1968). They improve cardiac performance (Downing et al., 1969) and mobilize glucose (Jones and Ritchie 1978). They stimulate absorption of the lung liquid and enhance the release of surfactant (Lawson et al., 1978), just to mention a few of the vital contributions to neonatal cardiopulmonary function.
MYOCARDIAL STRUCTURE AND FUNCTION
Structural and functional studies of the fetal and neonatal lamb's myocardium (Friedman 1972, McPherson et al., 1976) demonstrated an inherent limitation of contractility during this age period. A higher resting tension was found in the fetal and neonatal lamb myocardium when compared with that of the sheep. There were fewer contractile elements but more nuclear material and water content in the myocardium of the fetus and newborn. Rapid postnatal growth of the left ventricle occurs which provides more "reserve" sarcomeres to handle the increasing blood volume and end-diastolic pressure. This was demonstrated both structurally and functionally in lambs (Riemenschneider et al., 1978) thus providing the basis for the age-related improvement of the contractile response of the neonatal myocardium to stretch according to Starling's law.
In the human newborn, Arcilla et al. (1966) have observed the absence of a post-extrasystolic potentiating effect in ventricular contraction which contrasted with findings in older children. This suggests a less well developed myocardial contractility in the newborn. Based on findings of a higher preejection period/left ventricular ejection time ratio, Hedvall (1975) concluded that left ventricular function in the newborn infant is impaired.
An interesting finding is the increase in preejection period/left ventricular ejection time ratio from birth to 4-to-6 hours of age in neonates (Lundell and Wallgren 1981). This might be explained by the diminishing concentration of catecholamines in the blood of the newborn.
Another possible explanation may be the relative decline in energy substrate for the heart. The energy source for the myocardium is conceivably influenced by the dramatic biochemical alterations during and after birth. The blood glucose level in fullterm infants decreases during the first 2 to 6 hours postnatally (Cornblath and Schwartz, 1966) when the infants are usually fasting. This may depress myocardial function and contribute to the increase in preejection period/left ventricular ejection time ratio in infants at this age.
The amount of myocardial glycogen is normally high throughout gestation (30-40 mg/g in the cardiac ventricles in human) (Fig.8) and these stores increase at term (Shelley, 1961). In the presence of severe postnatal hypoxia, survival depends to a certain extent on anaerobic energy release (Stafford and Weatherall, 1960).
THE PLACENTAL TRANSFUSION
One circulatory parameter that has attracted a great deal of interest in its physiological implication on the adaptive capacity of the neonate is placental transfusion. When cord clamping is delayed for 3-5 min. ("late-clamped") and blood volume (BV) determined 8-15 minutes after birth, there is an increment of about 33% compared with infants whose cords were clamped within 10 sec. of birth ("early-clamped"), or a 25% increment in BV when measured at 1/2-hour-old (Oh et al., 1966). Based on red cell volume, a more satisfactory indicator of the magnitude of placental transfusion, a 40-50% blood volume increase was estimated in late-clamped infants (Usher et al., 1963). The late-clamped infant adjusts to a larger blood volume by hemoconcentration, rapid plasma extravasation and increased urine output during the first hours of life (Oh et al., 1966). Considerable differences in the circulatory and respiratory function, between infants with small and large placental transfusion, have been noted during the first days of life.
The sudden augmentation in BV in late-clamped infants was observed to be reflected even in the more distensible venous part of the circulatory system. During the first hour of life, the atrial pressures of the late-clamped infants are higher. Thereafter, the difference between the two groups is not significant. The atrial pressures of late-clamped infants drop to about half by the 2nd hour or later, whereas that of the early-clamped infants remains unchanged at comparable ages (Arcilla et al., 1966). A blood volume related pulmonary hypertension exists in the late-clamped infants and a further hypertensive effect may be elicited by the prevailing lower Pa02 and higher PaC02 in these infants (Oh et al., 1966).
There is also a difference in systemic blood pressure between early- and late-clamped infants (Oh et al., 1966). The latter have a relatively high systolic pressure at 5 min. of life followed by a rapid decline during the first 6 hours. In early-clamped infants, the systolic pressure starts at a much lower level to be followed by a slight rise during the first 15 min. Both groups show a low systemic blood flow during the 1st day which increases by the 2nd or 3rd day, accompanied by a decline in systemic vascular resistance.
Left-to-right shunts and, to a lesser degree, right-to-left shunts persist longer postnatally in the late-clamped infants, suggesting that closure of the fetal channels may occur later (Arcilla et al., 1967).
Unlike the early-clamped infants, the late-clamped ones are not always entirely asymptomatic and expiratory grunting is not uncommon (Yao et al., 1971) during the first hours after birth.
It has further been found that the preejection period is prolonged in late-clamped infants suggesting that a sizable placenta-transfusion affects adversely the left ventricular performance of the neonate (Yao and Lind 1799).
Concluding excuse: Ars longa -- vita brevis. This review presents only relatively few studies of the overwhelmingly rich literature on the perinatal circulation.
Figure 1. Dawes (1954) classic illustration of the postnatal changes in the circulation.
Figure 2. The effects of changes in Pot, in pH alone and in both combined, on the pulmonary vascular resistance as derived from studies in newborn calves (Rudolph and Yuan 1966).
Figure 3. The shunt through the ductus arteriosus and the relationship between systemic and pulmonary resistance (Wallgren 1977).
Figure 4. Inner ductal diameter (X ± S.D.) is shown immediately after delivery and up to 120 min. afterwards in control pups and those exposed in utero to indomethacin by dosing the dam either 18 or 12 h prior to delivery. Small numbers denote the number of determinations at each point (Sharpe, Thalme and Larsson 1974).
Figure 5. Oxygen saturation of the peripheral blood in relation to birth of the infant (Wallgren 1977).
Figure 6. Catecholamine concentrations and pH values in fetal scalp blood samples during labor and in umbilical artery at birth (0 min.): (a) Six normal deliveries with fetal pH <7.25; (b) six complicated deliveries with pH <7.25.
Figure 7. Catecholamine concentrations in umbilical arterial blood at birth, after uncomplicated vaginal delivery, elective and emergency caesarean sections. (Lagercrantz and Bistoletti unpublished data)
Figure 8. Cardiac carbohydrates and survival during.anoxia (Stafford and Weatherall 1960).
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