The cardiovascular transition at birth: the effect of UCC before lung aeration
Before birth, blood flow through the lungs is low as the majority of blood exiting the right ventricle by-passes the lungs and enters the thoracic aorta via the ductus arteriosus (DA) [6, 7, 14]. As a result, pulmonary venous return is also low and only provides a small proportion of the preload required to maintain left ventricular output in the fetus (Fig. 1). Instead, much of the preload for the left ventricle during fetal life is derived from umbilical venous return [6, 7, 14]. This blood flows from the umbilical vein, via the ductus venosus, inferior vena cava and through the foramen ovale to directly enter the left atrium [14]. The preferential streaming of well-oxygenated umbilical venous blood through the ductus venosus and foramen ovale into the left atrium, gives rise to higher oxygenation levels in fetal preductal (vs postductal) arteries [14].
While the fetal circulatory arrangement allows a relatively direct flow of oxygenated blood from the placenta into the left atrium, which is analogous to flow between the lungs and left atrium in adults (Fig. 1), UCC at birth can severely disrupt venous return and cardiac output [6, 7]. Indeed, UCC causes venous return to decrease by 30–50 %, which reduces preload and cardiac output by a similar amount [6, 7]. At the same time, total peripheral resistance increases with the loss of the low resistance placental circulation, which causes a rapid increase (30 % within 4 heart beats; Fig. 2) in arterial blood pressure [6, 15, 16]. No doubt this increase in afterload contributes to the decrease in cardiac output, which is reflected by both a decrease in stroke volume and a decrease in heart rate [6, 7] (Fig. 3). With regard to the latter, it is important to recognize that the low heart rates commonly observed at birth [17], even in normal term infants, may result from a loss of preload caused by UCC rather than from an acute hypoxic episode. Indeed, a recent study in rabbits has shown that ventilation with 100 % nitrogen also increases PBF and heart rate after birth [18]. Thus, an increase in oxygen is unlikely to be the only stimulus for the increase in heart rate at birth, which also likely involves an increase in PBF via an increase in preload [1].
Effect of umbilical cord clamping (dotted line) on carotid arterial blood pressure (CAP) in three lambs. CAP increases by ~30 % in 4–5 heart beats [6]
Heart rate and right ventricular output measured in newborn lambs that either had their umbilical cords clamped 1–2 mins before ventilation was commenced (clamp first; closed circles) or were ventilated and pulmonary blood flow allowed to increase before their cords were clamped (vent first; open circles). The broken line (a) indicates either when cord clamping occurred in the clamp first group or ventilation commenced in the vent first group. The broken line (b), indicates when either clamping occurred in the vent first group or when ventilation commenced in the clamp first group. Data were obtained from [6] and redrawn
While the precise mechanisms by which lung aeration stimulates the increase in PBF at birth are still unclear [19], a recent imaging study has shown that lung aeration and the increase in PBF are not spatially related [20]. This study showed that partial lung aeration caused a global increase in PBF, leading to a large ventilation/perfusion mismatch in unaerated regions of the lung (Fig. 4). A follow up study showed that this global increase in PBF in response to partial lung aeration also occurs following ventilation with 100 % nitrogen [18]. These unexpected findings suggest that the dominant mechanisms involved are different to the mechanisms regulating regional PBF in the adult and that while oxygen must play a role [21], other mechanisms are also involved. Nevertheless, as PBF becomes the sole source of preload for the left ventricle after birth, PBF must increase shortly after UCC to replace umbilical venous return as the primary source of preload for the left ventricle [6]. As such, if there is a delay between UCC and the onset of lung aeration, the infant will not only be exposed to hypoxia, due to a lack of gas exchange, but also to a prolonged period of reduced or restricted cardiac output. As the primary physiological defense mechanism that is invoked during hypoxia is an increase and redistribution of cardiac output [22–24], this period of reduced cardiac output puts the infant at high risk of hypoxic/ischemic injury. On the other hand, if ventilation onset coincides with or immediately follows UCC, any reduction in cardiac output is likely to be brief and greatly reduced.
A combined angiographic and phase contrast X-ray image of a near term (30 days) rabbit kitten that was delivered by caesarean section and received unilateral ventilation of the right lung. Blood flow, as shown by the contrast agent in the pulmonary vessels, increases similarly in both the aerated right lung and the unaerated left lung
It is also important to consider how the infant’s physiology responds to UCC and the sudden reduction in cardiac output combined with a rapid (over 4 heart beats; Fig. 2) increase in arterial blood pressure (afterload) [6]. As the cerebral circulation is pressure passive over this time frame, this increase in pressure leads to an increase in cerebral blood flow in lambs. However, as cardiac output is also decreased, after ~60 s arterial blood pressure and cerebral blood flow also decrease before stabilizing (after ~2mins), presumably due to a baroreceptor mediated peripheral vasoconstriction [6]. Then after ventilation onset, the sudden increase in PBF restores left ventricular preload and increases cardiac output, leading to a second rapid increase in arterial blood pressure and cerebral blood flow (Fig. 3); increases in cardiac output have also been observed in human infants at birth [25, 26]. The net result of UCC followed by lung aeration after a brief delay (1–2 mins), are large fluctuations in arterial pressure and cerebral blood flow [6]. It is also interesting that right ventricular output rapidly increases with cardiac output following lung aeration, suggesting that left-to-right shunting through the foramen ovale may contribute to right ventricular preload at this time (Fig. 3).
Another consideration with regard to the impact of UCC at birth and the associated reduction in cardiac output, is the question of how PBF increases so rapidly and to such a large extent when right and left ventricular output are initially both low. The answer is partly due to the redirection of right ventricular output through the lungs, rather than through the DA, as pulmonary vascular resistance (PVR) decreases [6, 7, 14]. In addition, because UCC greatly increases peripheral vascular resistance, the decrease in PVR makes the lungs a lower resistance pathway for blood flow compared to the systemic circulation. As a result, blood flow through the DA reverses, leading to left-to-right shunting of blood from the aorta into the pulmonary artery, which makes a significant contribution to the increase in PBF [7]. While the net flow is left-to-right, instantaneous flow is bi-directional at different times throughout the cardiac cycle [7, 27]. This is because the pressure waves emanating from the left and right ventricles reach the pulmonary and aortic ends of the DA at different times after the onset of systole. During early systole, right ventricular contraction produces a pressure gradient across the DA that leads initially to right-to-left flow across the DA. However, as the pressure wave emanating from the left ventricle reaches the DA-aortic junction, the pressure gradient reverses, which produces left-to-right flow through the DA that is sustained throughout most of diastole. Interestingly, the net left-to-right flow through the DA leads to a partial left ventricle-lung-left ventricle short circuit [7]. Presumably this allows the two ventricles time (while the DA closes) to gradually balance their outputs after birth, which ensures that the left ventricle is not deprived of preload during this transitional period.