CIRCULATORY SYSTEM Umbilical Circulation Umbilical blood flow is dependent on the vascular resistance and the pressure gradients created through the descending aorta, the placental circulation, and the inferior vena cava. In fetal lambs, blood pressure in the umbilical artery slowly increases through gestation to 55 or 65 mm Hg, although the pressure in the umbilical vein remains at about 10-12 mm Hg. The increased volume of the vascular bed of the placenta in late gestation accounts for the increased pressure drop across the placenta over this time. In human infants, although the transitions are similar, the umbilical vein retains a pressure of nearly 25 mm Hg at term. The increasing arterial pressure allows an increase in blood flow almost proportional to fetal growth, which further allows oxygen consumption to increase in proportion to body weight. Umbilical arteries are reactive to a variety of stimuli; vasoconstriction may be induced by high oxygen tension, tactile stimulation, or cold, while vasodilation occurs in response to high CO2 tensions or low oxygen tensions. However, in vivo, umbilical vessels show almost no direct local effect in response to large changes in blood gas tensions. The intra-abdominal portion of the umbilical vein is highly innervated, however, the degree of innervation of the extraabdominal portion is much lower and may be absent. Development of the Circulatory System The embryo is unable to sustain growth beyond a few millimeters without a mechanism for transporting gases, nutrients, and waste products. Therefore, the fetal cardiovascular system is the first organ system to become functional in the developing fetus. By 3-4 weeks of age, the heart is moving blood through the 2 mm embryo. By eight weeks of age, the partition of the heart and its major arterial trunks is complete. At birth, the relative weight of the heart is 0.7% of total body weight, as compared to 0.4% in the adult. In the 15 mm embryo, heart rate is about 65 beats/minute. It peaks at 175 beats/minute at 9 weeks of age in human fetuses, slowing to 135 to 155 beats per minute at term. Variability in the fetal heart rate will persist into adult life. Moreover, the slower the resting rate, the faster the poststimulus rate, a trait that is also carried into postnatal life. During fetal life, blood flow is shunted to the systemic arterial system via the ductus arteriosus and ductus venosus. Oxygen rich umbilical venous blood (80% saturated with oxygen) enters the right atrium of the heart via the ductus venosus and the inferior vena cava. About 50% of venous return enters the inferior vena cava through the ductus venosus, allowing it bypass the portal circulation and function as a low-resistance bypass to the heart. This blood then crosses the oval foramen into the left atrium, left ventricle and systemic arterial circulation to provide this oxygen-rich blood to the head, brain, and upper body. Poorly oxygenated blood (< 60% saturated with oxygen) entering the superior vena cava is directed is directed almost entirely through the tricuspid valve into the right ventricle across the ductus arteriosus (because pulmonary resistance is so high) to the aorta from which it is reoxygenated by the placental circulation. At birth, the ductus arteriosus and ductus venosus close, and with the rapid increase in pulmonary blood flow, the left atrial pressure increases resulting in functional closure of the oval foramen. This closure, however, is reversible for the fist few days of life. For example, crying fits in infants create a right-left shunt, inducing cyanotic periods. It takes nearly a year in infants for full fusion to occur, and in 25% of all individuals, anatomical closure is never complete. The heart transforms from two pumps functioning partly in parallel to two pumps functioning in series. The oxygenation and gaseous expansion of the lung mediates pulmonary arterial dilation, decreasing pulmonary resistance, and an increase in pulmonary blood flow. Arachidonic acid metabolites including prostaglandins I2 and E2 and inhibition of leukotriene synthesis are all potent vasodilators at birth and may contribute to the decrease in pulmonary arterial pressure. Systemic pressure increases, and regional blood flows shift in response to oxygen requirements. The loss of the resistance due to the placental circulation also contributes to greatly altered regional flows. The net result is that the lung receives a ten-fold increase in blood flow after closure of the ductus arteriosus. Closure of the ductus venosus is triggered after the partial pressure of oxygen exceeds ~55 mm Hg, and is thought to be mediated primarily by bradykinins released from pulmonary tissue during initial inflation after birth. The immediate postnatal changes in the circulation are associated with an increased cardiac output. The mechanism for this is not fully known but fetal sheep that have been thyroidectomized two weeks prior to delivery do not show this same increase. The prenatal increase in thyroid hormones prior to birth may stimulate -adrenergic receptor development in the heart making it responsive to the increased concentrations of catecholamines at birth. Ventilation, oxygenation, decreases in the right ventricular mechanical constraints, and umbilical cord occlusion may all contribute to the catecholamine-induced increase in ventricular output and in heart rate at birth. Newborns are particularly susceptible to modest increases in oxygen transport capabilities or demands because of the high resting oxygen demands and a limited reserve for increasing cardiac output or oxygen extraction. Oxygen uptake is relatively high in newborns compared to the fetus. A limited preload reserve and high heart rate in the newborn that is faced with stress do not permit adequate increases in cardiac output. Additionally, there is often a decrease in hemoglobin concentrations postnatally (decreasing oxygen carrying capacity of the blood) and fractional oxygen extraction is limited by the high percentage of fetal hemoglobin present. Timing of Umbilical Cord Rupture Blood flow continues through the placenta for approximately 1.5 min after the first breath; constriction of umbilical vessels and stoppage of placental flow (as well as initiation of placental separation) is initiated primarily by the change in oxygen tension associated with the shift from placental to pulmonary respiration. Transfer of placental blood into the fetal system is not complete until this umbilical constriction occurs. Placental transfusion is accomplished by a combination of vessel constriction within the placental vascular bed (effectively reducing vascular capacity), uterine contractions, and gravity. The umbilical arteries close prior to the umbilical veins, allowing placental blood to continue to flow into the fetus after fetal blood has stopped flowing to the placenta. Gravity is an important consideration in humans; if the infant is held above the level of the placenta, reverse flow can occur. A smaller residual volume of blood will remain in the placenta if the cord is clamped after respiration has been initiated. Expansion of the pulmonary vascular bed will require about 10-20% of the neonatal blood volume, which in itself will serve to draw in more placental blood as systemic pressure is reduced accordingly. Either placental transfusion or fetal blood loss can occur at delivery; both can have dramatic effects on blood volume and clinical outcomes in the neonate. The benefits or risks associated with delaying clamping of the umbilical cord have been debated for nearly fifty years. The definitions applied to early- and late-clamping of the cord has created much variation in the literature, and data interpretation is complicated. Early clamping has been applied at any time from delivery of the buttocks to 1 minute after birth, while late clamping has been applied to anything from the first breath to 5 or more minutes. Obviously, what is considered late-clamping by some researchers has been considered early by others. However, for our purposes, we will consider delayed clamping to be anything beyond a minute and early as anything earlier than a minute after birth; keep in mind there is considerable variation within the parameters applied to the data presented and it may seem to be inconsistent. Delayed umbilical cord clamping in premature infants results in increased packed cell volume and arterial-alveolar oxygen tension differences and decreased reliance on supplemental oxygen. Placental transfusion in infants can increase blood volume by ~ 100 ml and the available iron pool by ~32 mg at a time when anemia is a common problem. The transfusion allows an increase from 20-60% of original blood volume. Respiration is initiated earlier if the umbilical cord is clamped early, although respiration rates are similar during the first 30 minutes after birth. However, by three hours of age, late-clamped infants have a faster rate of respiration which persists at least for the next several days. Transfused infants also have lower lung compliance and a smaller functional residual capacity. Transudation of plasma into the highly vascular pulmonary epithelium does occur, however, no causal relationship has been established between the degree of transudation and incidence of respiratory distress syndrome. Concerns have been raised as to the ability of the neonate to cope with this added volume of blood; this is of special concern in premature infants. Heart load may increase beyond the capacity of the newborn to adapt and left-right shunts may be re-established. Within 30 minutes, fluid shifts occur from intravascular to extravascular pools; these shifts take about 12 hours to complete in infants. The transudation of plasma may account for up to 50% of initial blood volume in late-clamped infants but is not seen to occur at all in early-clamped infants. Central and portal venous pressures average 5.7 mm Hg in late-clamped and 1.7 mm Hg in earlyclamped infants. Systolic pressures are higher for the first 6 hours of life in late-clamped infants. Pulmonary pressures are 90% of aortic pressures in late-clamped infants during the first day of life and less than 70% in early-clamped infants. These increased pressures create a large workload for the neonatal heart. In infants where the cord is clamped early (within seconds of delivery), changes in the electrocardiogram after birth are different than in late-clamped (3 minutes after birth) infants. Early clamped infants have a slower and narrower range of heart rate during the first hours of life and a greater increase in rate after a cry than late-clamped infants. They also have shorter intervals (P duration, P-R segment, P-R interval, QRS duration, Q-Tc), lower deflections (PII, QV6, RV6, SV6, TV1). Earlier inversion of the T wave in V1, and a higher T wave in V6 on the first day of life. The P wave differences are still apparent at the end of the first week of life. In extremely premature infants, aggressive cord-stripping has been reported to cause cardiac failure, presumably from volume overload. In addition, respiratory distress has been reported to occur in infants with high blood hematocrits or increased blood viscosity. Renal response to this high volume load is important. Urine flow is significantly higher in late-clamped infants through the first 12 hours of life; in this same period, the glomerular filtration rate is also higher. . In cattle, the relatively short umbilical cord often ruptures as the hind legs are expelled from the birth canal. Assistance to these calves often ruptures the umbilical cord earlier than would occur in an unassisted delivery. Stressed calves demonstrate delayed behavioral adaptations, irregular respiration rates, and failure to thermoregulate; these same clinical problems were reported by Mahaffey (1961) as responses to premature rupture of the umbilical vessels in both foals and lambs. Premature rupture resulted in a loss of ~1500 ml of placental blood in foals, roughly 30% of the total blood volume at birth. The decreased blood volume was theorized to result in decreased ability to perfuse vital organs, especially the pulmonary system and the central nervous system, inducing many of the clinical outcomes observed in these neonates. The same loss in blood volume has been reported in infants with placenta previa or abruptio placenta, and has been theorized as a major cause of death in infants born from these types of pregnancies. Deficits in oxygen delivery in these infants leads to a much higher incidence of permanent neurological deficit. Cesarian-derived infants are typically pulled from a non-contracting uterus and placed on their mother’s abdomen prior to clamping the cord. This can result in significant blood loss; plasma volume is ~35 ml/kg, red cell volume is ~31 ml/kg, and blood volume is ~66 ml/kg. Delaying clamping for 3 minutes while holding the infant below the level of the placenta increases blood volume and red cell volume by 20%. Distressed infants subjected to emergency cesarian section have blood volumes more closely resembling infants from a normal vaginal delivery.